Lactam compounds and their use as pharmaceuticals

ABSTRACT

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 11/269,984,filed Nov. 9, 2005, which claims the benefit of U.S. Ser. Nos.60/626,617, filed Nov. 10, 2004 and 60/715,020, filed Sep. 8, 2005, thedisclosures of each of which are incorporated herein by reference intheir entities.

FIELD OF THE INVENTION

The present invention relates to modulators of 11-β hydroxyl steroiddehydrogenase type 1 (11βHSD1) and/or mineralocorticoid receptor (MR),compositions thereof and methods of using the same.

BACKGROUND OF THE INVENTION

Glucocorticoids are steroid hormones that regulate fat metabolism,function and distribution. In vertebrates, glucocorticoids also haveprofound and diverse physiological effects on development, neurobiology,inflammation, blood pressure, metabolism and programmed cell death. Inhumans, the primary endogenously-produced glucocorticoid is cortisol.Cortisol is synthesized in the zona fasciculate of the adrenal cortexunder the control of a short-term neuroendocrine feedback circuit calledthe hypothalamic-pituitary-adrenal (HPA) axis. Adrenal production ofcortisol proceeds under the control of adrenocorticotrophic hormone(ACTH), a factor produced and secreted by the anterior pituitary.Production of ACTH in the anterior pituitary is itself highly regulated,driven by corticotropin releasing hormone (CRH) produced by theparaventricular nucleus of the hypothalamus. The HPA axis maintainscirculating cortisol concentrations within restricted limits, withforward drive at the diurnal maximum or during periods of stress, and israpidly attenuated by a negative feedback loop resulting from theability of cortisol to suppress ACTH production in the anteriorpituitary and CRH production in the hypothalamus.

Aldosterone is another hormone produced by the adrenal cortex;aldosterone regulates sodium and potassium homeostasis. Fifty years ago,a role for aldosterone excess in human disease was reported in adescription of the syndrome of primary aldosteronism (Conn, (1955), J.Lab. Clin. Med. 45: 6-17). It is now clear that elevated levels ofaldosterone are associated with deleterious effects on the heart andkidneys, and are a major contributing factor to morbidity and mortalityin both heart failure and hypertension.

Two members of the nuclear hormone receptor superfamily, glucocorticoidreceptor (GR) and mineralocorticoid receptor (MR), mediate cortisolfunction in vivo, while the primary intracellular receptor foraldosterone is the MR. These receptors are also referred to as‘ligand-dependent transcription factors,’ because their functionality isdependent on the receptor being bound to its ligand (for example,cortisol); upon ligand-binding these receptors directly modulatetranscription via DNA-binding zinc finger domains and transcriptionalactivation domains.

Historically, the major determinants of glucocorticoid action wereattributed to three primary factors: 1) circulating levels ofglucocorticoid (driven primarily by the HPA axis), 2) protein binding ofglucocorticoids in circulation, and 3) intracellular receptor densityinside target tissues. Recently, a fourth determinant of glucocorticoidfunction was identified: tissue-specific pre-receptor metabolism byglucocorticoid-activating and -inactivating enzymes. These11-beta-hydroxysteroid dehydrogenase (11-β-HSD) enzymes act aspre-receptor control enzymes that modulate activation of the GR and MRby regulation of glucocorticoid hormones. To date, two distinct isozymesof 11-beta-HSD have been cloned and characterized: 11βHSD1 (also knownas 11-beta-HSD type 11betaHSD1, HSD11B1, HDL, and HSD11L) and 11βHSD2.11βHSD1 and 11βHSD2 catalyze the interconversion of hormonally activecortisol (corticosterone in rodents) and inactive cortisone(11-dehydrocorticosterone in rodents). 11βHSD1 is widely distributed inrat and human tissues; expression of the enzyme and corresponding mRNAhave been detected in lung, testis, and most abundantly in liver andadipose tissue. 11βHSD1 catalyzes both 11-beta-dehydrogenation and thereverse 11-oxoreduction reaction, although 11βHSD1 acts predominantly asa NADPH-dependent oxoreductase in intact cells and tissues, catalyzingthe activation of cortisol from inert cortisone (Low et al. (1994) J.Mol. Endocrin. 13: 167-174) and has been reported to regulateglucocorticoid access to the GR. Conversely, 11βHSD2 expression is foundmainly in mineralocorticoid target tissues such as kidney, placenta,colon and salivary gland, acts as an NAD-dependent dehydrogenasecatalyzing the inactivation of cortisol to cortisone (Albiston et al.(1994) Mol. Cell. Endocrin. 105: R11-R17), and has been found to protectthe MR from glucocorticoid excess, such as high levels ofreceptor-active cortisol (Blum, et al., (2003) Prog. Nucl. Acid Res.Mol. Biol. 75:173-216).

In vitro, the MR binds cortisol and aldosterone with equal affinity. Thetissue specificity of aldosterone activity, however, is conferred by theexpression of 11βHSD2 (Funder et al. (1988), Science 242: 583-585). Theinactivation of cortisol to cortisone by 11βHSD2 at the site of the MRenables aldosterone to bind to this receptor in vivo. The binding ofaldosterone to the MR results in dissociation of the ligand-activated MRfrom a multiprotein complex containing chaperone proteins, translocationof the MR into the nucleus, and its binding to hormone response elementsin regulatory regions of target gene promoters. Within the distalnephron of the kidney, induction of serum and glucocorticoid induciblekinase-1 (sgk-1) expression leads to the absorption of Na ions and waterthrough the epithelial sodium channel, as well as potassium excretionwith subsequent volume expansion and hypertension (Bhargava et al.,(2001), Endo 142: 1587-1594).

In humans, elevated aldosterone concentrations are associated withendothelial dysfunction, myocardial infarction, left ventricularatrophy, and death. In attempts to modulate these ill effects, multipleintervention strategies have been adopted to control aldosteroneoveractivity and attenuate the resultant hypertension and its associatedcardiovascular consequences. Inhibition of angiotensin-converting enzyme(ACE) and blockade of the angiotensin type 1 receptor (AT1R) are twostrategies that directly impact the rennin-angiotensin-aldosteronesystem (RAAS). However, although ACE inhibition and AT1R antagonisminitially reduce aldosterone concentrations, circulating concentrationsof this hormone return to baseline levels with chronic therapy (known as‘aldosterone escape’). Importantly, co-administration of the MRantagonist Spironolactone or Eplerenone directly blocks the deleteriouseffects of this escape mechanism and dramatically reduces patientmortality (Pitt et al., New England J. Med. (1999), 341: 709-719; Pittet al., New England J. Med. (2003), 348: 1309-1321). Therefore, MRantagonism may be an important treatment strategy for many patients withhypertension and cardiovascular disease, particularly those hypertensivepatients at risk for target-organ damage.

Mutations in either of the genes encoding the 1-beta-HSD enzymes areassociated with human pathology. For example, 11βHSD2 is expressed inaldosterone-sensitive tissues such as the distal nephron, salivarygland, and colonic mucosa where its cortisol dehydrogenase activityserves to protect the intrinsically non-selective MR from illicitoccupation by cortisol (Edwards et al. (1988) Lancet 2: 986-989).Individuals with mutations in 11βHSD2 are deficient in thiscortisol-inactivation activity and, as a result, present with a syndromeof apparent mineralocorticoid excess (also referred to as ‘SAME’)characterized by hypertension, hypokalemia, and sodium retention (Wilsonet al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Likewise,mutations in 11βHSD1, a primary regulator of tissue-specificglucocorticoid bioavailability, and in the gene encoding a co-localizedNADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), canresult in cortisone reductase deficiency (CRD), in which activation ofcortisone to cortisol does not occur, resulting inadrenocorticotropin-mediated androgen excess. CRD patients excretevirtually all glucocorticoids as cortisone metabolites(tetrahydrocortisone) with low or absent cortisol metabolites(tetrahydrocortisols). When challenged with oral cortisone, CRD patientsexhibit abnormally low plasma cortisol concentrations. These individualspresent with ACTH-mediated androgen excess (hirsutism, menstrualirregularity, hyperandrogenism), a phenotype resembling polycystic ovarysyndrome (PCOS) (Draper et al. (2003) Nat. Genet. 34: 434-439).

The importance of the HPA axis in controlling glucocorticoid excursionsis evident from the fact that disruption of homeostasis in the HPA axisby either excess or deficient secretion or action results in Cushing'ssyndrome or Addison's disease, respectively (Miller and Chrousos (2001)Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, NewYork), 4^(th) Ed.: 387-524). Patients with Cushing's syndrome (a raredisease characterized by systemic glucocorticoid excess originating fromthe adrenal or pituitary tumors) or receiving glucocorticoid therapydevelop reversible visceral fat obesity. Interestingly, the phenotype ofCushing's syndrome patients closely resembles that of Reaven's metabolicsyndrome (also known as Syndrome X or insulin resistance syndrome) thesymptoms of which include visceral obesity, glucose intolerance, insulinresistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven(1993) Ann. Rev. Med. 44: 121-131). However, the role of glucocorticoidsin prevalent forms of human obesity has remained obscure becausecirculating glucocorticoid concentrations are not elevated in themajority of metabolic syndrome patients. In fact, glucocorticoid actionon target tissue depends not only on circulating levels but also onintracellular concentration, locally enhanced action of glucocorticoidsin adipose tissue and skeletal muscle has been demonstrated in metabolicsyndrome. Evidence has accumulated that enzyme activity of 11βHSD1,which regenerates active glucocorticoids from inactive forms and plays acentral role in regulating intracellular glucocorticoid concentration,is commonly elevated in fat depots from obese individuals. This suggestsa role for local glucocorticoid reactivation in obesity and metabolicsyndrome.

Given the ability of 11βHSD1 to regenerate cortisol from inertcirculating cortisone, considerable attention has been given to its rolein the amplification of glucocorticoid function. 11βHSD1 is expressed inmany key GR-rich tissues, including tissues of considerable metabolicimportance such as liver, adipose, and skeletal muscle, and, as such,has been postulated to aid in the tissue-specific potentiation ofglucocorticoid-mediated antagonism of insulin function. Considering a)the phenotypic similarity between glucocorticoid excess (Cushing'ssyndrome) and the metabolic syndrome with normal circulatingglucocorticoids in the latter, as well as b) the ability of 11βHSD1 togenerate active cortisol from inactive cortisone in a tissue-specificmanner, it has been suggested that central obesity and the associatedmetabolic complications in syndrome X result from increased activity of11βHSD1 within adipose tissue, resulting in ‘Cushing's disease of theomentum’ (Bujalska et al. (1997) Lancet 349: 1210-1213). Indeed, 11βHSD1has been shown to be upregulated in adipose tissue of obese rodents andhumans (Livingstone et al. (2000) Endocrinology 131: 560-563; Rask etal. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421; Lindsay et al.(2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J.Clin. Endocrinol. Metab. 88: 3983-3988).

Additional support for this notion has come from studies in mousetransgenic models. Adipose-specific overexpression of 11βHSD1 under thecontrol of the aP2 promoter in mouse produces a phenotype remarkablyreminiscent of human metabolic syndrome (Masuzaki et al. (2001) Science294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90).Importantly, this phenotype occurs without an increase in totalcirculating corticosterone, but rather is driven by a local productionof corticosterone within the adipose depots. The increased activity of11βHSD1 in these mice (2-3 fold) is very similar to that observed inhuman obesity (Rask et al. (2001) J. Clin. Endocrinol. Metab. 86:1418-1421). This suggests that local 11βHSD1-mediated conversion ofinert glucocorticoid to active glucocorticoid can have profoundinfluences whole body insulin sensitivity.

Based on this data, it would be predicted that the loss of 11βHSD1 wouldlead to an increase in insulin sensitivity and glucose tolerance due toa tissue-specific deficiency in active glucocorticoid levels. This is,in fact, the case as shown in studies with 11βHSD1-deficient miceproduced by homologous recombination (Kotelevstev et al. (1997) Proc.Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem.276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938). These miceare completely devoid of 11-keto reductase activity, confirming that11βHSD1 encodes the only activity capable of generating activecorticosterone from inert 11-dehydrocorticosterone. 11βHSD1-deficientmice are resistant to diet- and stress-induced hyperglycemia, exhibitattenuated induction of hepatic gluconeogenic enzymes (PEPCK, G6P), showincreased insulin sensitivity within adipose, and have an improved lipidprofile (decreased triglycerides and increased cardio-protective HDL).Additionally, these animals show resistance to high fat diet-inducedobesity. Taken together, these transgenic mouse studies confirm a rolefor local reactivation of glucocorticoids in controlling hepatic andperipheral insulin sensitivity, and suggest that inhibition of 11βHSD1activity may prove beneficial in treating a number ofglucocorticoid-related disorders, including obesity, insulin resistance,hyperglycemia, and hyperlipidemia.

Data in support of this hypothesis has been published. Recently, it wasreported that 11βHSD1 plays a role in the pathogenesis of centralobesity and the appearance of the metabolic syndrome in humans.Increased expression of the 11βHSD1 gene is associated with metabolicabnormalities in obese women and that increased expression of this geneis suspected to contribute to the increased local conversion ofcortisone to cortisol in adipose tissue of obese individuals (Engeli, etal., (2004) Obes. Res. 12: 9-17).

A new class of 11βHSD1 inhibitors, the arylsulfonamidothiazoles, wasshown to improve hepatic insulin sensitivity and reduce blood glucoselevels in hyperglycemic strains of mice (Barf et al. (2002) J. Med.Chem. 45: 3813-3815; Alberts et al. Endocrinology (2003) 144:4755-4762). Furthermore, it was recently reported that selectiveinhibitors of 11βHSD1 can ameliorate severe hyperglycemia in geneticallydiabetic obese mice. Thus, 11βHSD1 is a promising pharmaceutical targetfor the treatment of the Metabolic Syndrome (Masuzaki, et al., (2003)Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62).

A. Obesity and Metabolic Syndrome

As described above, multiple lines of evidence suggest that inhibitionof 11βHSD1 activity can be effective in combating obesity and/or aspectsof the metabolic syndrome cluster, including glucose intolerance,insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia.Glucocorticoids are known antagonists of insulin action, and reductionsin local glucocorticoid levels by inhibition of intracellular cortisoneto cortisol conversion should increase hepatic and/or peripheral insulinsensitivity and potentially reduce visceral adiposity. As describedabove, 11βHSD1 knockout mice are resistant to hyperglycemia, exhibitattenuated induction of key hepatic gluconeogenic enzymes, show markedlyincreased insulin sensitivity within adipose, and have an improved lipidprofile. Additionally, these animals show resistance to high fatdiet-induced obesity (Kotelevstev et al. (1997) Proc. Natl. Acad. Sci.94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300;Morton et al. (2004) Diabetes 53: 931-938). Thus, inhibition of 11βHSD1is predicted to have multiple beneficial effects in the liver, adipose,and/or skeletal muscle, particularly related to alleviation ofcomponent(s) of the metabolic syndrome and/or obesity.

B. Pancreatic Function

Glucocorticoids are known to inhibit the glucose-stimulated secretion ofinsulin from pancreatic beta-cells (Billaudel and Sutter (1979) Horm.Metab. Res. 11: 555-560). In both Cushing's syndrome and diabetic Zuckerfafa rats, glucose-stimulated insulin secretion is markedly reduced(Ogawa et al. (1992) J. Clin. Invest. 90: 497-504). 11βHSD1 mRNA andactivity has been reported in the pancreatic islet cells of ob/ob miceand inhibition of this activity with carbenoxolone, an 11βHSD1inhibitor, improves glucose-stimulated insulin release (Davani et al.(2000) J. Biol. Chem. 275: 34841-34844). Thus, inhibition of 11βHSD1 ispredicted to have beneficial effects on the pancreas, including theenhancement of glucose-stimulated insulin release.

C. Cognition and Dementia

Mild cognitive impairment is a common feature of aging that may beultimately related to the progression of dementia. In both aged animalsand humans, inter-individual differences in general cognitive functionhave been linked to variability in the long-term exposure toglucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1: 69-73). Further,dysregulation of the HPA axis resulting in chronic exposure toglucocorticoid excess in certain brain subregions has been proposed tocontribute to the decline of cognitive function (McEwen and Sapolsky(1995) Curr. Opin. Neurobiol. 5: 205-216). 11βHSD1 is abundant in thebrain, and is expressed in multiple subregions including thehippocampus, frontal cortex, and cerebellum (Sandeep et al. (2004) Proc.Natl. Acad. Sci. Early Edition: 1-6). Treatment of primary hippocampalcells with the 11βHSD1 inhibitor carbenoxolone protects the cells fromglucocorticoid-mediated exacerbation of excitatory amino acidneurotoxicity (Rajan et al. (1996) J. Neurosci. 16: 65-70).Additionally, 11βHSD1-deficient mice are protected fromglucocorticoid-associated hippocampal dysfunction that is associatedwith aging (Yau et al. (2001) Proc. Natl. Acad. Sci. 98: 4716-4721). Intwo randomized, double-blind, placebo-controlled crossover studies,administration of carbenoxolone improved verbal fluency and verbalmemory (Sandeep et al. (2004) Proc. Natl. Acad. Sci. Early Edition:1-6). Thus, inhibition of 11βHSD1 is predicted to reduce exposure toglucocorticoids in the brain and protect against deleteriousglucocorticoid effects on neuronal function, including cognitiveimpairment, dementia, and/or depression.

D. Intra-Ocular Pressure

Glucocorticoids can be used topically and systemically for a wide rangeof conditions in clinical opthamology. One particular complication withthese treatment regimens is corticosteroid-induced glaucoma. Thispathology is characterized by a significant increase in intra-ocularpressure (IOP). In its most advanced and untreated form, IOP can lead topartial visual field loss and eventually blindness. IOP is produced bythe relationship between aqueous humour production and drainage. Aqueoushumour production occurs in the non-pigmented epithelial cells (NPE) andits drainage is through the cells of the trabecular meshwork. 11βHSD1has been localized to NPE cells (Stokes et al. (2000) Invest. Opthalmol.Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Opthalmol. Vis. Sci.42: 2037-2042) and its function is likely relevant to the amplificationof glucocorticoid activity within these cells. This notion has beenconfirmed by the observation that free cortisol concentration greatlyexceeds that of cortisone in the aqueous humour (14:1 ratio). Thefunctional significance of 11βHSD1 in the eye has been evaluated usingthe inhibitor carbenoxolone in healthy volunteers (Rauz et al. (2001)Invest. Opthalmol. Vis. Sci. 42: 2037-2042). After seven days ofcarbenoxolone treatment, IOP was reduced by 18%. Thus, inhibition of11βHSD1 in the eye is predicted to reduce local glucocorticoidconcentrations and IOP, producing beneficial effects in the managementof glaucoma and other visual disorders.

E. Hypertension

Adipocyte-derived hypertensive substances such as leptin andangiotensinogen have been proposed to be involved in the pathogenesis ofobesity-related hypertension (Matsuzawa et al. (1999) Ann. N.Y. Acad.Sci. 892: 146-154; Wajchenberg (2000) Endocr. Rev. 21: 697-738). Leptin,which is secreted in excess in aP2-11βHSD1 transgenic mice (Masuzaki etal. (2003) J. Clinical Invest. 112: 83-90), can activate varioussympathetic nervous system pathways, including those that regulate bloodpressure (Matsuzawa et al. (1999) Ann. N.Y. Acad. Sci. 892: 146-154).Additionally, the renin-angiotensin system (RAS) has been shown to be amajor determinant of blood pressure (Walker et al. (1979) Hypertension1: 287-291). Angiotensinogen, which is produced in liver and adiposetissue, is the key substrate for renin and drives RAS activation. Plasmaangiotensinogen levels are markedly elevated in aP2-11βHSD1 transgenicmice, as are angiotensin II and aldosterone (Masuzaki et al. (2003) J.Clinical Invest. 112: 83-90). These forces likely drive the elevatedblood pressure observed in aP2-11βHSD1 transgenic mice. Treatment ofthese mice with low doses of an angiotensin II receptor antagonistabolishes this hypertension (Masuzaki et al. (2003) J. Clinical Invest.112: 83-90). This data illustrates the importance of localglucocorticoid reactivation in adipose tissue and liver, and suggeststhat hypertension may be caused or exacerbated by 11βHSD1 activity.Thus, inhibition of 11βHSD1 and reduction in adipose and/or hepaticglucocorticoid levels is predicted to have beneficial effects onhypertension and hypertension-related cardiovascular disorders.

F. Bone Disease

Glucocorticoids can have adverse effects on skeletal tissues. Continuedexposure to even moderate glucocorticoid doses can result inosteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447)and increased risk for fractures. Experiments in vitro confirm thedeleterious effects of glucocorticoids on both bone-resorbing cells(also known as osteoclasts) and bone forming cells (osteoblasts).11βHSD1 has been shown to be present in cultures of human primaryosteoblasts as well as cells from adult bone, likely a mixture ofosteoclasts and osteoblasts (Cooper et al. (2000) Bone 27: 375-381), andthe 11βHSD1 inhibitor carbenoxolone has been shown to attenuate thenegative effects of glucocorticoids on bone nodule formation (Bellows etal. (1998) Bone 23: 119-125). Thus, inhibition of 11βHSD1 is predictedto decrease the local glucocorticoid concentration within osteoblastsand osteoclasts, producing beneficial effects in various forms of bonedisease, including osteoporosis.

Small molecule inhibitors of 11βHSD1 are currently being developed totreat or prevent 11βHSD1-related diseases such as those described above.For example, certain amide-based inhibitors are reported in WO2004089470, WO 2004089896, WO 2004056745, and WO 2004/065351.

Antagonists of 11βHSD1 have been evaluated in human clinical trials(Kurukulasuriya, et al., (2003) Curr. Med. Chem. 10: 123-53).

In light of the experimental data indicating a role for 11βHSD1 inglucocorticoid-related disorders, metabolic syndrome, hypertension,obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2diabetes, androgen excess (hirsutism, menstrual irregularity,hyperandrogenism) and polycystic ovary syndrome (PCOS), therapeuticagents aimed at augmentation or suppression of these metabolic pathways,by modulating glucocorticoid signal transduction at the level of 11βHSD1are desirable.

Furthermore, because the MR binds to aldosterone (its natural ligand)and cortisol with equal affinities, compounds that are designed tointeract with the active site of 11βHSD1 (which binds tocortisonecortisol) may also interact with the MR and act as antagonists.Because the MR is implicated in heart failure, hypertension, and relatedpathologies including atherosclerosis, arteriosclerosis, coronary arterydisease, thrombosis, angina, peripheral vascular disease, vascular walldamage, and stroke, MR antagonists are desirable and may also be usefulin treating complex cardiovascular, renal, and inflammatory pathologiesincluding disorders of lipid metabolism including dyslipidemia orhyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia,hypercholesterolemia, hypertriglyceridemia, as well as those associatedwith type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome, andinsulin resistance, and general aldosterone-related target-organ damage.

As evidenced herein, there is a continuing need for new and improveddrugs that target 11βHSD1 and/or MR. The compounds, compositions andmethods described herein help meet this and other needs.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent members are defined herein.

The present invention further provides compositions comprising compoundsof the invention and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating 11βHSD1 orMR by contacting 11βHSD1 or MR with a compound of the invention.

The present invention further provides methods of inhibiting 11βHSD1 orMR by contacting 11βHSD1 or MR with a compound of the invention.

The present invention further provides methods of inhibiting theconversion of cortisone to cortisol in a cell by contacting the cellwith a compound of the invention.

The present invention further provides methods of inhibiting theproduction of cortisol in a cell by contacting the cell with a compoundof the invention.

The present invention further provides methods of treating diseasesassociated with activity or expression of 11βHSD1 or MR.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salt or prodrug thereof, wherein:

Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 —W—X—Y-Z;

L is (CR¹²R¹³)_(q1), (CR¹²R¹³)_(q1)O(CR¹²R¹³)_(q2),(CR¹²R¹³)_(q1)S(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2),(CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), or (CR¹²R¹³)_(q1)CO(CR¹²R¹³)_(q2);

Q is —(CR¹R²)_(m)-A;

A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′;

E is —(CR^(3a)R^(3b))_(n1)—, —(CR^(3a)R^(3b))_(n2)CO—,—(CR^(3a)R^(3b))_(n2)OCO—, —(CR^(3a)R^(3b))_(n2)SO—,—(CR^(3a)R^(3b))_(n2)SO₂—, —(CR^(3a)R^(3b))_(n2)NR^(3c)—,—(CR^(3a)R^(3b))_(n3)CONR^(3c)—, —(CR^(3a)R^(3b))_(n2)NR^(3c)CO—, or agroup of formula:

D¹, D², D³ and D⁴ are each N or CR¹⁵;

R¹ and R² are each, independently, H or C₁₋₈ alkyl;

R^(3a) and R^(3b) are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′),C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′),NR^(C′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′),S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), halo, C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted by R¹⁶;

R^(3c) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, orCO—(C₁₋₄ alkyl);

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each, independently, H,OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′),NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(c′)C(O)OR^(b′), S(O)R^(a′),S(O)NR^(c′)R^(d′), S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′),halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted byR¹⁴;

or R⁴ and R⁵ together with the carbon atom to which they are attachedform a 3-14 membered cycloalkyl or heterocycloalkyl group which isoptionally substituted by R¹⁴;

or R⁶ and R⁷ together with the carbon atom to which they are attachedform a 3-14 membered cycloalkyl or heterocycloalkyl group which isoptionally substituted by R¹⁴;

or R⁸ and R⁹ together with the carbon atom to which they are attachedform a 3-14 membered cycloalkyl or heterocycloalkyl group which isoptionally substituted by R¹⁴;

or R¹⁰ and R¹¹ together with the carbon atom to which they are attachedform a 3-14 membered cycloalkyl or heterocycloalkyl group which isoptionally substituted by R¹⁴;

or R⁴ and R⁶ together with the carbon atom to which they are attachedform a 3-7 membered fused cycloalkyl group or 3-7 membered fusedheterocycloalkyl group which is optionally substituted by R¹⁴;

or R⁶ and R⁸ together with the carbon atom to which they are attachedform a 3-7 membered fused cycloalkyl group or 3-7 membered fusedheterocycloalkyl group which is optionally substituted by R¹⁴;

or R⁴ and R⁹ together form a C₁₋₃ alkylene bridge which is optionallysubstituted by R¹⁴;

or R⁴ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionallysubstituted by R¹⁴;

or R⁶ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionallysubstituted by R¹⁴;

or R⁹ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionallysubstituted by R¹⁴;

R¹² and R¹³ are each, independently, H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂,OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′),OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), orS(O)₂NR^(c′)R^(d′);

R¹⁴ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′),C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′),NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′),S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′)R^(d′);

R¹⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″),C(O)NR^(c″R) ^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″),NR^(c″)R^(d″), NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″),S(O)NR^(c″)R^(d″), S(O)₂R^(b″), or S(O)₂NR^(c″)R^(d″);

R¹⁶ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′),C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′),NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′),S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′R) ^(d′);

W, W′ and W″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂,SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino;

X, X′ and X″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl, wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl isoptionally substituted by one or more halo, oxo, CN, NO₂, OH, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

Y, Y′ and Y″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂,SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino;

Z, Z′ and Z″ are each, independently, H, halo, CN, NO₂, OH, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionallysubstituted by 1, 2 or 3 halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(d), NR^(e)S(O)₂R^(b), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), or S(O)₂NR^(c)R^(d);

wherein two —W—X—Y-Z attached to the same atom optionally form a 3-20membered cycloalkyl or heterocyloalkyl group, each optionallysubstituted by 1, 2 or 3 —W″—X″—Y″-Z″;

wherein two —W′—X′—Y′-Z′ attached to the same atom optionally form a3-20 membered cycloalkyl or heterocyloalkyl group, each optionallysubstituted by 1, 2 or 3 —W″—X″—Y″-Z″;

wherein —W—X—Y-Z is other than H;

wherein —W′—X′—Y′-Z′ is other than H;

wherein —W″—X″—Y″-Z″ is other than H;

R^(a), R^(a′) and R^(a″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;heterocycloalkyl, heterocycloalkylalkyl is optionally substituted withH, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

R^(b), R^(b′) and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or heterocycloalkyl;

R^(c) and R^(d) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or heterocycloalkyl;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(c′) and R^(d′) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or heterocycloalkyl;

or R^(c′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(c″) and R^(d″) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or heterocycloalkyl;

or R^(c″) and R^(d″) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(e) and R^(f) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or heterocycloalkyl;

or R^(e) and R^(f) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

m is 0, 1, 2 or 3;

n1 is 1, 2, 3 or 4;

n2 is 0, 1, 2, 3 or 4;

n3 is 0, 1, 2, 3 or 4;

p is 0, 1 or 2;

q1 is 0, 1 or 2;

q2 is 0, 1 or 2; and

r is 0, 1 or 2.

In some embodiments, when A is aryl optionally substituted with 1, 2, 3,4 or 5 —W′—X′—Y′-Z′ or heteroaryl optionally substituted with 1, 2, 3, 4or 5 —W′—X′—Y′-Z′; L is SO₂, SO₂CH₂ or CH₂; and m is 0, then Cy is otherthan unsubstituted aryl, mono substituted aryl, unsubstitutedheteroaryl, or monosubstituted heteroaryl.

In some embodiments, when A is aryl optionally substituted with 1, 2, 3,4 or 5 —W′—X′—Y′-Z′ or heteroaryl optionally substituted with 1, 2, 3, 4or 5 —W′—X′—Y′-Z′; L is SO₂, SO₂CH₂ or CH₂; m is 0; and Cy is di-, tri-,tetra- or penta-substituted aryl or di-, tri-, tetra- orpenta-substituted heteroaryl, then said di-, tri-, tetra- orpenta-substituted aryl or di-, tri-, tetra- or penta-substitutedheteroaryl is substituted by at least one C₁₋₆ alkyl and at least onehalo.

In some embodiments, when A is aryl optionally substituted with 1, 2, 3,4 or 5 —W′—X′—Y′-Z′ or heteroaryl optionally substituted with 1, 2, 3, 4or 5 —W′—X′—Y′-Z′; L is SO₂, SO₂CH₂ or CH₂; and m is 0, then Cy is otherthan 2-chloro-6-methyl-phenyl.

In some embodiments, when A is phenyl or 4-phenoxyphenyl; L is SO₂ orSO₂CH₂; and m is 0 or 1, then Cy is other than cyclohexyl or1,1-dioxo-tetrahydro-thien-3-yl.

In some embodiments, when Cy is aryl optionally substituted with 1, 2,3, 4 or 5 —W—X—Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4or 5 —W—X—Y-Z; L is SO₂, SO₂CH₂ or CH₂; and m is 0, then A is other thantetrahydropyran-4-yl, 2,3-dihydroinden-2-yl or2,2-difluoro-1,3-benzodioxol-5-yl.

In some embodiments, when Cy is aryl optionally substituted with 1, 2,3, 4 or 5 —W—X—Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4or 5 —W—X—Y-Z; L is SO₂, SO₂CH₂ or CH₂; and m is 1, then A is other thanpyridine-4-yl, phenyl, 2-chloro-6-fluoro-phenyl, 4-methoxyphenyl or4-phenoxy-phenyl.

In some embodiments, R^(3a) and R^(3b) are each, independently, H, halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl.

In some embodiments, X, X′ and X″ are each, independently, absent, C₁₋₆alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl,heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkylenyl, C₂₋₆alkenylenyl, C₂₋₆ alkynylenyl, cycloalkyl, heteroaryl orheterocycloalkyl is optionally substituted by one or more halo, oxo, CN,NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino.

In some embodiments, Z, Z′ and Z″ are each, independently, H, halo, CN,NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl isoptionally substituted by 1, 2 or 3 halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), orS(O)₂NR^(c)R^(d).

In some embodiments, when r is 1 and R⁴ and R⁵ together with the carbonatom to which they are attached form a 3, 4, 5 or 6-memberedheterocycloalkyl group, then m is other than 1.

In some embodiments, Cy is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4 or 5-W—X—Y-Z.

In some embodiments, Cy is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4 or 5-W—X—Y-Z wherein W is O or absent, X isabsent, and Y is absent.

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl,triazinyl, furanyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl,quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or1,3-benzothiazolyl, each optionally substituted with 1, 2, 3, 4 or 5—W—X—Y-Z.

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl,triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, 3,4 or 5 —W—X—Y-Z.

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl,triazinyl, furanyl thiazolyl, pyrazinyl, purinyl, quinazolinyl,quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 halo,CN, NO₂, C₁₋₄ alkoxy, heteroaryloxy, C₂₋₆ alkynyl, C₁₋₄ haloalkoxy,NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d),NR^(e)S(O)₂R^(b), C₁₋₄ haloalkyl, C₁₋₆ alkyl, heterocycloalkyl, aryl orheteraryl, wherein each of said C₁₋₆ alkyl, aryl or heteraryl isoptionally substituted by 1, 2 or 3 halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl,CN, NO₂, OR^(a), SR^(a), C(O)NR^(c)R^(d), NR^(c)C(O)R^(d) or COOR^(a).

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl,triazinyl, furanyl thienyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl,quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4substituents independently selected form:

halo, CN, NO₂, C₁₋₄ alkoxy, pyridin-2-yloxy, pyridin-3-yloxy,pyridin-4-yloxy, C₂₋₆ alkynyl, C₁₋₄ haloalkoxy, NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(e)S(O)₂R^(b),C₁₋₄haloalkyl, C₁₋₆ alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl,pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl,2-oxo-[1,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl,2-oxopiperidinyl, and 2-oxo-[1,3]oxazinanyl; wherein each of said C₁₋₆alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl,1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl,2-oxo-[1,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl,2-oxopiperidinyl, or 2-oxo-[1,3]oxazinanyl is optionally substituted by1, 2 or 3 halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)NR^(c)R^(d), NR^(c)C(O)R^(d) or COOR^(a).

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl,triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or3 halo, CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl or aryl, whereinsaid C₁₋₆ alkyl or aryl is optionally substituted by 1, 2 or 3 halo,C₁₋₆ alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a), or SR^(a).

In some embodiments, Cy is phenyl, naphthyl, pyridyl, pyrimidinyl,triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or3 halo, CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl or aryl, whereinsaid C₁₋₆ alkyl or aryl is optionally substituted by 1, 2 or 3 halo orC₁₋₆ alkyl.

In some embodiments, Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, orisoquinolinyl, each optionally substituted with 1, 2, 3, 4 or 5—W—X—Y-Z.

In some embodiments, Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, orisoquinolinyl, each optionally substituted with 1, 2, or 3 halo, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, —NR^(e)C(O)O-Z, —C(O)O-Z, orNR^(e)C(O)-Z.

In some embodiments, Cy is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.

In some embodiments, Cy is piperidinyl, pyrrolindinyl,1,2,3,6-tetrahydropyridinyl, 2-oxo-[1,3]oxazinanyl, or piperizinyl, eachoptionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.

In some embodiments, Cy is piperidinyl, pyrrolindinyl,1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substitutedwith 1, 2, 3, 4 or 5 —W—X—Y-Z.

In some embodiments, Cy is piperidinyl, pyrrolindinyl,1,2,3,6-tetrahydropyridinyl, 2-oxo-[1,3]oxazinanyl, or piperizinyl, eachoptionally substituted with 1, 2, or 3 aryl or heteroaryl, wherein eachof said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo,CN, C₁₋₄ alkyl, phenyl, pyridyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkyl.

In some embodiments, Cy is piperidinyl, pyrrolindinyl,1,2,3,6-tetrahydropyridinyl, 2-oxo-[1,3]oxazinanyl, or piperizinyl, eachoptionally substituted with 1, 2, or 3 phenyl, pyridyl or quinolinyl,wherein each of said phenyl, pyridyl, quinolinyl is optionallysubstituted by 1, 2 or 3 halo, CN, C₁₋₄ alkyl, phenyl, C₁₋₄ alkoxy, orC₁₋₄ haloalkyl.

In some embodiments, Cy is piperidinyl, pyrrolindinyl,1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substitutedwith 1, 2, or 3 aryl, wherein said aryl is optionally substituted by 1,2 or 3 halo or C₁₋₄ haloalkyl.

In some embodiments, L is (CR¹²R¹³)_(q1)S(CR¹²R¹³)_(q2),(CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), or (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2).

In some embodiments, L is (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2).

In some embodiments, L is S, SO or SO₂.

In some embodiments, L is SO₂.

In some embodiments, L is CO.

In some embodiments, L is (CR¹²R¹³)_(q1).

In some embodiments, L is (CR¹²R¹³)_(q1) and q1 is 0.

In some embodiments, Q is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5—W′—X′—Y′-Z′.

In some embodiments, Q is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4 or 5 halo, C₁₋₄ alkyl, CN, NR^(c)C(O)R^(d)or NR^(e)S(O)₂R^(b).

In some embodiments, Q is phenyl, pyridyl or quinolinyl, each optionallysubstituted with 1 or 2 halo, C₁₋₄ alkyl, CN, NR^(c)C(O)R^(d) orNR^(e)S(O)₂R^(b).

In some embodiments, Q is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′.

In some embodiments, Q is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1 or 2 —W′—X′—Y′-Z′.

In some embodiments, Q is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 OH, C₁₋₄ alkoxy, CN, C₁₋₄alkyl, —O-heteroaryl, —(C₁₋₄ alkyl)-CN, COOR^(a), C(O)NR^(c)R^(d) orNR^(c)C(O)OR^(a).

In some embodiments, Q is cyclopropyl, cyclohexyl, cycloheptyl,adamantyl, tetrahydro-2H-pyranyl or piperidinyl, each optionallysubstituted with 10H, C₁₋₄ alkoxy, CN, C₁₋₄ alkyl, —O-heteroaryl, —(C₁₋₄alkyl)-CN, COOR^(a), C(O)NR^(c)R^(d) or NR^(c)C(O)OR^(a).

In some embodiments, Q is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, C₁₋₄ alkyl,C₁₋₄ alkoxy, NR^(e)COO(C₁₋₄ alkyl), NR^(e)CO(C₁₋₄ alkyl), aryl,heteroaryl, —O-aryl, —O-heteroaryl, or —(C₁₋₄alkyl)-OH.

In some embodiments, Q is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 OH, CN, —O-heteroaryl, orC(O)O-Z′.

In some embodiments, Q is cycloalkyl or heterocycloalkyl, eachsubstituted with at least two —W′—X′—Y′-Z′, wherein two of said at leasttwo —W′—X′—Y′-Z′ are attached to the same atom and together with theatom to which they are attached form a 3-20 membered cycloalkyl orheterocyloalkyl group, each optionally substituted by 1, 2 or 3—W″—X″—Y″-Z″.

In some embodiments, Q is phenyl, pyridyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3,4 or 5 —W′—X′—Y′-Z′.

In some embodiments, Q is phenyl, pyridyl, cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with1, 2, 3, 4 or 5 OH, CN, halo, C₁₋₆ alkyl, —O-heteroaryl, or C(O)O-Z′.

In some embodiments, Q is cyclohexyl substituted at the 4-position withat least one —W′—X′—Y′-Z′.

In some embodiments, Q is cyclohexyl substituted at the 4-position withat least one OH, CN, or —O—X′—Y′-Z′.

In some embodiments, Q is —(CR¹R²)_(m)-A and m is 1, 2 or 3.

In some embodiments, Q is —(CR¹R²)_(m)-A and m is 2.

In some embodiments, A is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4 or 5-W′—X′—Y′-Z′.

In some embodiments, A is aryl optionally substituted with 1, 2, 3, 4 or5 —W′—X′—Y′-Z′.

In some embodiments, A is heteroaryl optionally substituted with 1, 2,3, 4 or 5 —W′—X′—Y′-Z′.

In some embodiments, A is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′.

In some embodiments, A is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1 or 2 —W′—X′—Y′-Z′.

In some embodiments, A is cycloalkyl optionally substituted with 1, 2,3, 4 or 5 —W′—X′—Y′-Z′.

In some embodiments, A is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, C₁₋₄ alkyl,C₁₋₄ alkoxy, NR^(e)COO(C₁₋₄ alkyl), NR^(e)CO(C₁₋₄ alkyl), aryl,heteroaryl, —O-aryl, —O-heteroaryl, or —(C₁₋₄ alkyl)-OH.

In some embodiments, A is cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4or 5 OH, CN, halo, C₁₋₆ alkyl, —O-heteroaryl, or C(O)O-Z′.

In some embodiments, A is cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4or 5 OH, CN, halo, C₁₋₆ alkyl, —O-heteroaryl, or C(O)O—(C₁₋₄ alkyl).

In some embodiments, A is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 OH, CN, —O-heteroaryl, orC(O)O-Z′.

In some embodiments, A is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4 or 5 OH, CN, —O-heteroaryl, orC(O)O—(C₁₋₄ alkyl).

In some embodiments, A is cycloalkyl or heterocycloalkyl, eachsubstituted with at least two —W′—X′—Y′-Z′, wherein two of said at leasttwo —W′—X′—Y′-Z′ are attached to the same atom and together with theatom to which they are attached form a 3-20 membered cycloalkyl orheterocyloalkyl group, each optionally substituted by 1, 2 or 3—W″—X″—Y″-Z″.

In some embodiments, A is phenyl, pyridyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3,4 or 5 —W′—X′—Y′-Z′.

In some embodiments, A is phenyl, pyridyl, cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with1, 2, 3, 4 or 5 OH, CN, halo, C₁₋₆ alkyl, —O-heteroaryl, or C(O)O-Z′.

In some embodiments, A is phenyl, pyridyl, cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with1, 2, 3, 4 or 5 OH, CN, halo, C₁₋₆ alkyl, —O-heteroaryl, or C(O)O—(C₁₋₄alkyl).

In some embodiments, A is cyclohexyl substituted at the 4-position withat least one —W′—X′—Y′-Z′.

In some embodiments, A is cyclohexyl substituted at the 4-position withat least one OH, CN, or —O—X′—Y′-Z′.

In some embodiments, E is methylene, ethylene, or propylene.

In some embodiments, E is ethylene.

In some embodiments, E is —(CR^(3a)R^(3b))_(n3)CONR^(3c)— or—(CR^(3a)R^(3b))_(n2)NR^(3c)CO—.

In some embodiments, E is —CONR^(3c)—.

In some embodiments, E is —CONR^(3c)—, wherein R^(3c) is H, C₁₋₄ alkyl,or CO—(C₁₋₄ alkyl).

In some embodiments, E is CONH—.

In some embodiments, E is a group of formula:

In some embodiments, D¹, D², D³ and D⁴ are each CR⁵.

In some embodiments, one or two of D¹, D², D³ and D⁴ is N.

In some embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each,independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′),OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′),NR^(c′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′),S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl.

In some embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each,independently, H, C₁₋₁₀ alkyl or C₁₋₁₀ haloalkyl.

In some embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each H.

In some embodiments, R^(3a) and R^(3b) are each H.

In some embodiments, r is 1.

In some embodiments, r is 0.

In some embodiments, the sum of q1 and q2 is 0, 1 or 2.

In some embodiments, the sum of q1 and q2 is 0.

In some embodiments, R¹² and R¹³ are each H.

In some embodiments, at least one of R¹ and R² is C₁₋₄ alkyl.

In some embodiments, m is 0.

In some embodiments, m is 1 or 2.

In some embodiments, n1 is 1.

In some embodiments, n1 is 2.

In some embodiments, n2 is 0.

In some embodiments, n2 is 1.

In some embodiments, n3 is 0.

In some embodiments, n3 is 1, 2, 3 or 4;

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, each —W—X—Y-Z is, independently, —NR^(e)C(O)O-Z,—C(O)O-Z, —NR^(e)C(O)-Z, —CO-Z, —SO-Z, —SO₂-Z, —SONR^(e)-Z,—NR^(e)CONR^(f)-Z, halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d).

In some embodiments, each —W—X—Y-Z is, independently, —NHC(O)O—C₁₋₄alkyl, —NHC(O)O—C₁₋₄ alkynyl, C(O)O—C₁₋₄ alkyl, —NHC(O)—C₁₋₄ alkyl,—NHC(O)—C₃₋₉ cycloalkyl, halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a)S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d).

In some embodiments, each —W—X—Y-Z is, independently, halo, CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, —NR^(e)C(O)O-Z, —C(O)O-Z,—NR^(e)C(O)-Z or aryl, wherein said aryl is optionally substituted by 1,2 or 3 halo or C₁₋₄ haloalkyl.

In some embodiments, each —W—X—Y-Z is, independently, halo, CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, —NHC(O)O—(C₁₋₄ alkyl),—NHC(O)O—(C₁₋₄ alkynyl), —C(O)O—(C₁₋₄ alkyl), —NHC(O)—(C₁₋₄ alkyl),—NHC(O)—(C₃₋₉ cycloalkyl) or phenyl, wherein said phenyl is optionallysubstituted by 1, 2 or 3 halo or C₁₋₄ haloalkyl.

In some embodiments, each —W—X—Y-Z is, independently, halo, CN, NO₂,C₁₋₄ alkoxy, heteroaryloxy, C₂₋₆ alkynyl, C₁₋₄ haloalkoxy,NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d),NR^(e)S(O)₂R^(b), C₁₋₄ haloalkyl, C₁₋₆ alkyl, heterocycloalkyl, aryl orheteraryl, wherein each of said C₁₋₆ alkyl, aryl or heteraryl isoptionally substituted by 1, 2 or 3 halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl,CN, NO₂, OR^(a), SR^(a), C(O)NR^(c)R^(d), NR^(c)C(O)R^(d) or COOR^(a).

In some embodiments, each —W—X—Y-Z is, independently, halo, CN, NO₂,C₁₋₄ alkoxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, C₂₋₆alkynyl, C₁₋₄ haloalkoxy, NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a),C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(e)S(O)₂R^(b), C₁₋₄ haloalkyl, C₁₋₆alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl,1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl,2-oxo-[1,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl,2-oxopiperidinyl, or 2-oxo-[1,3]oxazinanyl, wherein each of said C₁₋₆alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl,1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl,2-oxo-[1,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl,2-oxopiperidinyl, or 2-oxo-[1,3]oxazinanyl is optionally substituted by1, 2 or 3 halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)NR^(c)R^(d), NR^(c)C(O)R^(d) or COOR^(a).

In some embodiments, each —W—X—Y-Z is, independently, aryl orheteroaryl, wherein each of said aryl or heteroaryl is optionallysubstituted by 1, 2 or 3 halo, CN, C₁₋₄ alkyl, phenyl, pyridyl, C₁₋₄alkoxy, or C₁₋₄ haloalkyl.

In some embodiments, each —W—X—Y-Z is, independently, phenyl, pyridyl orquinolinyl, wherein each of said phenyl, pyridyl, quinolinyl isoptionally substituted by 1, 2 or 3 halo, CN, C₁₋₄ alkyl, phenyl, C₁₋₄alkoxy, or C₁₋₄ haloalkyl.

In some embodiments, each —W′—X′—Y′-Z′ is, independently, OH, CN, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —O-Z′, —C(O)-Z′ or —C(O)O-Z′, wherein said C₁₋₆ alkyl,aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are each optionallysubstituted by 1, 2 or 3 halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), orS(O)₂NR^(c)R^(d).

In some embodiments, each —W′—X′—Y′-Z′ is, independently, OH, C₁₋₄alkoxy, CN, C₁₋₄ alkyl, —O-heteroaryl, —(C₁₋₄ alkyl)-CN, COOR^(a),C(O)NR^(c)R^(d) or NR^(c)C(O)OR^(a).

In some embodiments, each —W′—X′—Y′-Z′ is, independently, halo, C₁₋₄alkyl, CN, NR^(c)C(O)R^(d) or NR^(e)S(O)₂R^(b).

In some embodiments, each —W′—X′—Y′-Z′ is, independently, OH, CN, halo,C₁₋₆ alkyl, —O-heteroaryl, or C(O)O-Z′.

In some embodiments, each —W′—X′—Y′-Z′ is, independently, OH, CN, halo,C₁₋₆ alkyl, —O-heteroaryl, or —C(O)O—C₁₋₄ alkyl.

In some embodiments, each —W″—X″—Y″-Z″ is halo, CN, NO₂, OH, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,NR^(e)S(O)₂R^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), NR^(e)S(O)₂R^(b), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d).

In some embodiments, each —W″—X″—Y″-Z″ is halo, CN, NO₂, OH, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionallysubstituted by 1, 2 or 3 halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), orS(O)₂NR^(c)R^(d).

In some embodiments, each —W″—X″—Y″-Z″ is halo, CN, NO₂, OH, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl.

In some embodiments, compounds of the invention have Formula II:

In some embodiments, compounds of the invention have Formula IIIa:

In some embodiments, compounds of the invention have Formula IIIb:

In some embodiments, compounds of the invention have Formula IIIc:

In some embodiments, compounds of the invention have Formula IV:

In some embodiments, compounds of the invention have Formula IVa:

In some embodiments, compounds of the invention have Formula IVb:

In some embodiments, compounds of the invention have Formula IVc:

In some embodiments, compounds of the invention have Formula IV, FormulaIVa, Formula IVb, or Formula IVc, wherein R^(3c) is H, C₁₋₄ alkyl, orCO—(C₁₋₄ alkyl). In some further embodiments, R^(3c) is H.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene isan example of a 10-membered cycloalkyl group.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms. The term “alkylenyl” refers to a divalent alkyl linkinggroup.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like. The term “alkenylenyl” refers to adivalent linking alkenyl group.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like. The term “alkynylenyl” refers to a divalentlinking alkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)groups. Ring-forming carbon atoms of a cycloalkyl group can beoptionally substituted by oxo or sulfido. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcamyl, adamantyl, and the like. Also included inthe definition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of pentane, pentene, hexane,and the like.

As used herein, “heteroaryl” refers to an aromatic heterocycle having atleast one heteroatom ring member such as sulfur, oxygen, or nitrogen.Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3or 4 fused rings) systems. Examples of heteroaryl groups include withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, and the like. In some embodiments, the heteroaryl group hasfrom 1 to about 20 carbon atoms, and in further embodiments from about 3to about 20 carbon atoms. In some embodiments, the heteroaryl groupcontains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6ring-forming atoms. In some embodiments, the heteroaryl group has 1 toabout 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to non-aromatic heterocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups where one or moreof the ring-forming carbon atoms is replaced by a heteroatom such as anO, N, or S atom. Heterocycloalkyl groups include monocyclic andpolycyclic (e.g., having 2, 3 or 4 fused rings) systems. Example“heterocycloalkyl” groups include morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-formingcarbon atoms and heteroatoms of a heterocycloalkyl group can beoptionally substituted by oxo or sulfido. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles such as indolene and isoindolenegroups. In some embodiments, the heterocycloalkyl group has from 1 toabout 20 carbon atoms, and in further embodiments from about 3 to about20 carbon atoms. In some embodiments, the heterocycloalkyl groupcontains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6ring-forming atoms. In some embodiments, the heterocycloalkyl group has1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments,the heterocycloalkyl group contains 0 to 3 double or triple bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 double ortriple bonds.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used here, “haloalkoxy” refers to an —O-haloalkyl group. An examplehaloalkoxy group is OCF₃.

As used herein, “heteroaryloxy” refers to O-heteroaryl. An exampleheteroaryloxy is pyridine-2-yloxy [i.e., O-(pyridine-2-yl)].

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An examplearylalkyl group is benzyl.

As used herein, “amino” refers to NH₂.

As used herein, “alkylamino” refers to an amino group substituted by analkyl group.

As used herein, “dialkylamino” refers to an amino group substituted bytwo alkyl groups.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms, such asketo-enol tautomers.

Compounds of the invention further include hydrates and solvates, aswell as anhydrous and non-solvated forms.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

The novel compounds of the present invention can be prepared in avariety of ways known to one skilled in the art of organic synthesis.The compounds of the present invention can be synthesized using themethods as hereinafter described below, together with synthetic methodsknown in the art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given; other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography.

Preparation of Compounds can Involve the Protection and Deprotection ofVarious Chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

The compounds of the invention can be prepared, for example, using thereaction pathways and techniques described below.

Compounds of the invention can be generally prepared by the methodoutlined in Scheme 1. Reagents of formula 1-1 (X is a leaving group suchas halo) can be reacted with an amines of formula 1-2 (or its salts) inan appropriate solvent (e.g., CH₂Cl₂) and optionally in the presence ofa base such as diisopropyl ethyl amine to provide the desired products1-3. As an example, sulfonyl chlorides of formula 1-4 can be reactedwith the amines of formula 1-2 to provide sulfonyl linked compounds offormula 1-5.

A series of spirocyclyl amines of formula 2-8 can be prepared accordingto the procedure outlined in Scheme 2. N-protected 2-1 (Pr is an aminoprotecting group such as Boc) can be treated with a base such as LDA atlow temperature in a solvent such as tetrahydrofuran followed byaddition of 1-bromo-3-methyl-2-butene (2-2). The resulting intermediate(2-3) can be treated with ozone and then reduced with methyl sulfide toprovide the aldehyde 2-4. Reductive amination of 2-4 with amines 2-5 canbe conducted in a solvent such as methanol and using a reducing agentsuch as sodium triacetoxyborohydride, and the product 2-6 can becyclized in the presence of a base such as isopropylmagnesium bromide toprovide the lactam 2-7 which upon acidic cleavage of the Boc groupyields the desired amine 2-8.

A series of amines of formula 3-7 can be prepared according to theprocedure outlined in Scheme 3. Treatment of Boc protected nipecoticethyl ester 3-1 with a base such as LDA at low temperature in a solventsuch as tetrahydrofuran followed by addition of1-bromo-3-methyl-2-butene can result in an intermediate 3-2, which canbe treated with ozone followed by reduction with methyl sulfide toprovide the aldehyde 3-3. Reductive amination of 3-3 with amines 3-4(where Q₁ is, e.g., substituted or unsubstituted cycloalkyl or aryl) canbe conducted in a solvent such as methanol and using a reducing agentsuch as sodium triacetoxyborohydride. The resulting intermediate 3-5 canbe cyclized in the presence of a base such as isopropylmagnesium bromideto provide the lactam 3-6 which upon acidic cleavage of the Boc groupyields the desired piperidine 3-7.

A series of piperidines of 4-4 can be prepared by the method outlined inScheme 4. Compound 4-1 can be readily converted to the spirohydantoin4-2 under Bucherer-Bergs conditions, using, e.g., ammonium carbonate andeither sodium cyanide or potassium cyanide in aqueous ethanol.Alkylation of compound 4-2 with one equivalent of alkyl halide QX (X isa leaving group such as halo) in the presence of potassium carbonate inDMF, followed by a second alkylation with R^(3c)X (X is a leaving groupsuch as halo) in the presence of sodium hydride in DMF providessubstituted hydantoins 4-3, which upon acidic cleavage of the Boc groupyields the desired piperidines 4-4.

Alternatively, treatment of compound 5-1 with alkyl amines R^(3c)NH₂ andsodium cyanidecan provide alkylated hydantoin derivatives 5-2. Aromaticsubstituted hydantoins 5-4 can be obtained by coupling compounds 5-2with aromatic boronic acids or aromatic halides 5-3 in the presence ofcatalyst. Acidic cleavage of the Boc group yields the desiredpiperidines 5-4 (Scheme 5).

In a further alternative route, piperidines 6-6 can also be prepared bythe method outlined in Scheme 6. The protected amino acid 6-1 can becoupled with an amine Q-NH₂ using a coupling agent such as BOP toprovide compound 6-2 which, in turn, can be hydrogenated at the presenceof Pd catalyst to yield compound 6-3. Compound 6-3 can be treated withmethyl chloroformate and a base such as triethyl amine in CH₂Cl₂ tocomplete the ring closure and form hydantoin 6-4. As describedpreviously, N alkylation with R^(3c)X (X is a leaving group such ashalo) can yield compounds of formula 6-5 and acid cleavage can yieldcompounds of formula 6-6.

Methods

Compounds of the invention can modulate activity of 11βHSD1 and/or MR.The term “modulate” is meant to refer to an ability to increase ordecrease activity of an enzyme or receptor. Accordingly, compounds ofthe invention can be used in methods of modulating 11βHSD1 and/or MR bycontacting the enzyme or receptor with any one or more of the compoundsor compositions described herein. In some embodiments, compounds of thepresent invention can act as inhibitors of 11βHSD1 and/or MR. In furtherembodiments, the compounds of the invention can be used to modulateactivity of 11βHSD1 and/or MR in an individual in need of modulation ofthe enzyme or receptor by administering a modulating amount of acompound of the invention.

The present invention further provides methods of inhibiting theconversion of cortisone to cortisol in a cell, or inhibiting theproduction of cortisol in a cell, where conversion to or production ofcortisol is mediated, at least in part, by 11βHSD1 activity. Methods ofmeasuring conversion rates of cortisone to cortisol and vice versa, aswell as methods for measuring levels of cortisone and cortisol in cells,are routine in the art.

The present invention further provides methods of increasing insulinsensitivity of a cell by contacting the cell with a compound of theinvention. Methods of measuring insulin sensitivity are routine in theart.

The present invention further provides methods of treating diseaseassociated with activity or expression, including abnormal activity andoverexpression, of 11βHSD1 and/or MR in an individual (e.g., patient) byadministering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. Example diseases caninclude any disease, disorder or condition that is directly orindirectly linked to expression or activity of the enzyme or receptor.An 11βHSD1-associated disease can also include any disease, disorder orcondition that can be prevented, ameliorated, or cured by modulatingenzyme activity.

Examples of 11βHSD1-associated diseases include obesity, diabetes,glucose intolerance, insulin resistance, hyperglycemia, hypertension,hyperlipidemia, cognitive impairment, dementia, depression (e.g.,psychotic depression), glaucoma, cardiovascular disorders, osteoporosis,and inflammation. Further examples of 11βHSD1-associated diseasesinclude metabolic syndrome, type 2 diabetes, androgen excess (hirsutism,menstrual irregularity, hyperandrogenism) and polycystic ovary syndrome(PCOS).

The present invention further provides methods of modulating MR activityby contacting the MR with a compound of the invention, pharmaceuticallyacceptable salt, prodrug, or composition thereof. In some embodiments,the modulation can be inhibition. In further embodiments, methods ofinhibiting aldosterone binding to the MR (optionally in a cell) areprovided. Methods of measuring MR activity and inhibition of aldosteronebinding are routine in the art.

The present invention further provides methods of treating a diseaseassociated with activity or expression of the MR. Examples of diseasesassociated with activity or expression of the MR include, but are notlimited to hypertension, as well as cardiovascular, renal, andinflammatory pathologies such as heart failure, atherosclerosis,arteriosclerosis, coronary artery disease, thrombosis, angina,peripheral vascular disease, vascular wall damage, stroke, dyslipidemia,hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia,hypercholesterolemia, hypertriglyceridemia, and those associated withtype 1 diabetes, type 2 diabetes, obesity metabolic syndrome, insulinresistance and general aldosterone-related target organ damage.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal. In some embodiments, the cell is an adipocyte, a pancreaticcell, a hepatocyte, neuron, or cell comprising the eye.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the 11βHSD1 enzyme with a compound of theinvention includes the administration of a compound of the presentinvention to an individual or patient, such as a human, having 11βHSD1,as well as, for example, introducing a compound of the invention into asample containing a cellular or purified preparation containing the11βHSD1 enzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomotology of the disease (non-limiting examples arepreventing metabolic syndrome, hypertension, obesity, insulinresistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgenexcess (hirsutism, menstrual irregularity, hyperandrogenism) andpolycystic ovary syndrome (PCOS);

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology)such as inhibiting the development of metabolic syndrome, hypertension,obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2diabetes, androgen excess (hirsutism, menstrual irregularity,hyperandrogenism) or polycystic ovary syndrome (PCOS), stabilizing viralload in the case of a viral infection; and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of metabolic syndrome, hypertension, obesity, insulinresistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgenexcess (hirsutism, menstrual irregularity, hyperandrogenism) andpolycystic ovary syndrome (PCOS), or lowering viral load in the case ofa viral infection.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of Formula I can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, antibodies, immunesuppressants, anti-inflammatory agents and the like.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in radio-imaging but also in assays, both in vitro andin vivo, for localizing and quantitating the enzyme in tissue samples,including human, and for identifying ligands by inhibition binding of alabeled compound. Accordingly, the present invention includes enzymeassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro receptor labeling and competition assays, compounds thatincorporate ³H, ⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled compound” is a compound that hasincorporated at least one radionuclide. In some embodiments theradionuclide is selected from the group consisting of 3H, ¹⁴C, ¹²⁵I, ³⁵Sand ⁸²Br.

In some embodiments, the labeled compounds of the present inventioncontain a fluorescent lable.

Synthetic methods for incorporating radio-isotopes and fluorescentlabels into organic compounds are well known in the art.

A labeled compound of the invention (radio-labeled, fluorescent-labeled,etc.) can be used in a screening assay to identify/evaluate compounds.For example, a newly synthesized or identified compound (i.e., testcompound) which is labeled can be evaluated for its ability to bind a11βHSD1 or MR by monitoring its concentration variation when contactingwith the 11βHSD1 or MR, through tracking the labeling. For anotherexample, a test compound (labeled) can be evaluated for its ability toreduce binding of another compound which is known to bind to 11βHSD1 orMR (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the11βHSD1 or MR directly correlates to its binding affinity. Conversely,in some other screening assays, the standard compound is labled and testcompounds are unlabeled. Accordingly, the concentration of the labledstandard compound is monitored in order to evaluate the competitionbetween the standard compound and the test compound, and the relativebinding affinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of 11βHSD1- or MR-associateddiseases or disorders, obesity, diabetes and other diseases referred toherein which include one or more containers containing a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the invention. Such kits can further include, if desired, one or moreof various conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results. The compound of the Examples were found to inhibitors of11βHSD1 and/or MR according to one or more of the assays providedherein.

EXAMPLES Example 1

7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-oneStep 1. 1-tert-butyl 3-ethyl3-(3-methylbut-2-en-1-yl)piperidine-1,3-dicarboxylate

To a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (2.6g, 10.0 mmol) in THF (30 mL) was slowly added LDA (6.7 mL, 12.0 mmol,1.8 M solution in heptane/tetrahydrofuran/ethylbenzene) at −78° C. andthe mixture was slowly warmed to −55° C. over 1 h. To this mixture,1-bromo-3-methyl-2-butene (1.55 g, 10.5 mmol) was slowly added and thereaction was warmed to room temperature and stirred for 4 h. The mixturewas quenched with saturated NH₄Cl and extracted with diethyl ether, andthe combined extracts were washed with brine, dried and concentrated.The product (2.75 g, 85%) was purified by CombiFlash eluted withhexane/ethyl acetate.

Step 2. 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate

1-tert-Butyl 3-ethyl3-(3-methylbut-2-en-1-yl)piperidine-1,3-dicarboxylate (2.75 g, 8.5 mmol)in CH₂Cl₂ (100 mL) was cooed to −78° C., and ozone was passed into thereaction mixture until a light blue color was observed (ca. 15 min).Nitrogen was then bubbled through the solution to remove the excessozone. Dimethyl sulfide (10 mL) was added and the reaction was slowlywarmed to room temperature and stirred overnight. The reaction was thenwashed with water and brine, dried and concentrated to give the product(2.5 g).

Step 3. J-tert-butyl 3-ethyl3-{2-[(cis-4-hydroxycyclohexyl)amino]ethyl}piperidine-1,3-dicarboxylate

DIPEA (1.05 eq.) was added to a solution of cis-4-aminocyclohexanolhydrochloride (0.080 g, 0.53 mmol) in methanol (2.0 mL) and stirred for5 min. To this solution 1-tert-butyl 3-ethyl3-(2-oxoethyl)-piperidine-1,3-dicarboxylate (0.15 g, 0.5 mmol) was addedfollowed by sodium triacetoxyborohydride (0.21 g, 1.0 mmol) and themixture was stirred for 2 h. The reaction was acidified by adding AcOHand diluted with water and extracted with ether. The aqueous phase wasthen basified by adding 1 N NaOH and extracted with ethyl acetate whichwas then washed with water then brine, dried, and concentrated to givethe desired product (0.17 g, 85%). LC-MS: 399.2 (M+H)⁺.

Step 4. tert-butyl2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate

iso-Propylmagnesium bromide (1.0 M in THF, 1.5 mL) was slowly added to asolution of 1-tert-butyl 3-ethyl3-{2-[(cis-4-hydroxycyclohexyl)amino]ethyl}piperidine-1,3-dicarboxylate(0.15 g, 0.38 mmol) at 0° C. and the mixture was stirred at thistemperature for 1 h. The reaction was then poured into cold water andextracted with ethyl acetate, dried and concentrated to give the desiredproduct (0.11 g, 85%). LC-MS: 353.2 (M+H)⁺, 297.1 (M+H-56)⁺.

Step 5. 2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride

Hydrogen chloride (2.0 mL, 4.0 M in 1,4-dioxane) was added to a solutionof tert-butyl2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate(0.10 g) in ethyl acetate (0.5 mL) at room temperature and the mixturewas stirred for 1 h. The solvent was then removed under vacuum to givethe product. LC-MS: 253.2 (M+H)⁺.

Step 6.7-[(3-chloro-2-methylphenyl)sulfonyl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

A solution of 3-chloro-2-methylbenzenesulfonyl chloride (0.050 g, 0.22mmol) in CH₂Cl₂ (110 mL) was slowly added to a mixture of2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride(0.060 g, 0.2 mmol) and DIPEA (0.10 mL, 0.6 mmol) in CH₂Cl₂ (110 mL) at0° C. and the reaction was stirred for 1 h. The mixture was diluted withethyl acetate and then washed with diluted HCl, water and brine, driedand concentrated. The product was purified by CombiFlash eluted withCH₂Cl₂/EtOAc. LC-MS: 441.2/443.2 (M+H)⁺.

Example 27-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those of forexample 1. LC-MS: 441.1/443.1 (M+H)⁺.

Example 37-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 433.1/435.1 (M+H)⁺.

Example 47-[(3-Chloro-2-methylphenyl)sulfonyl]-2-phenyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 419.2/421.2 (M+H)⁺.

Example 5Trans-4-{7-[(3-chloro-2-methylphenyl)sulfonyl]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 450.2/452.2 (M+H)⁺.

Example 67-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 439.1/441.1 (M+H)⁺.

Example 77-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 425.1/427.1 (M+H)⁺.

Example 87-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(4-methylpyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 434.1/435.1 (M+H)⁺.

Example 97-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-2-yloxy)cyclohexyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 518.2/520.2 (M+H)⁺.

Example 107-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-3-yloxy)cyclohexyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 518.2/520.2 (M+H)⁺.

Example 117-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-4-yloxy)cyclohexyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 518.2/520.2 (M+H)⁺.

Example 122-(1-Adamantyl)-7-[(3-chloro-2-methylphenyl)sulfonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 477.2/479.2 (M+H)⁺.

Example 137-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(1-methyl-2-phenylethyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those ofexample 1. LC-MS: 461.1/463.1 (M+H)⁺.

Example 14(5R)-7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using a chiral column to separate theenantiomers of example 6. Prep Chiral LC conditions: Column: ChiralCelOD-H, 20×250 mm, 5 μm (Chiral Technologies, Inc.); Mobile phase: 15%Ethanol/85% Hexanes; Flow rate: 15 mL/min; Detection: 220 nm; Retentiontime: t=7.22 min for peak 1; t=9.39 min for peak 2. This compoundcorresponded to peak 1. LC-MS: 439.1/441.1 (M+H)⁺.

Example 15(5S)-7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those for thesynthesis of example 14. This compound corresponded to peak 2 of thechiral column. LC-MS: 439.1/441.1 (M+H)⁺.

Example 16cis-4-{7-[(3-Chloro-2-methylphenyl)sulfony]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile

This compound was prepared using procedures analogous to those for thesynthesis of example 1. LC-MS: 450.2/452.2 (M+H)⁺.

Example 172-Cyclohexyl-7-(2-fluorophenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-5, followed bythe following microwave mediated amine/aryl coupling procedure:

A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride(0.025 g, 0.000092 mol), 1-bromo-2-fluorobenzene (0.032 g, 0.00018 mol),and sodium tert-butoxide (0.026 g, 0.00027 mol) in DMSO (0.5 mL) wasmicrowave irradiated at 180° C. for 5 min. After cooling the reactionmixture to ambient temperature the crude product was purified byprep.-HPLC. LC-MS: 331.2 (M+H)⁺.

Example 182-Cyclohexyl-7-(4-fluorophenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those for thesynthesis of example 17. LC-MS: 331.2 (M+H)⁺.

Example 192-Cyclohexyl-7-(3-fluorophenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those for thesynthesis of example 17. LC-MS: 331.2 (M+H)⁺.

Example 20 2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those for thesynthesis of example 17. LC-MS: 313.2 (M+H)⁺.

Example 217-(4-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those for thesynthesis of example 17. LC-MS: 347.2 (M+H)⁺.

Example 227-(3-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those for thesynthesis of example 17. LC-MS: 347.2 (M+H)⁺.

Example 232-(trans-4-Hydroxycyclohexyl)-7-phenyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those for thesynthesis of example 17. LC-MS: 329.2 (M+H)⁺.

Example 26 Methyl1-[7-(2-fluorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclopropanecarboxylate

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-3, followed bythe following reductive amination/cyclization and amine/aryl couplingprocedure as described in example 17:

1-Aminocyclopropanecarboxylic acid (0.10 g, 0.00099 mol) in MeOH (3 mL)with 4 N HCl (1.5 mL) was stirred at rt for 2 h. LCMS analysis indicatedthat the carboxylic acid was successfully converted to methyl ester.(m/z 116.3). The volatiles were removed in-vacuo to afford 150 mg of themethyl ester HCl salt. To this methyl ester, 1-tert-butyl 3-ethyl3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.25 g, 0.00084 mol), andtriethylamine (190 μL, 0.0013 mol) in 1,2-dichloroethane (1.5 mL, 0.019mol) was stirred at rt for 30 min. To the mixture was added sodiumtriacetoxyborohydride (0.35 g, 0.0017 mol) with stirring. After stirringat rt for 2 h, the reaction mixture then was heated to 70° C. andstirred for 16 h. LCMS data indicated that the spiro-ring formed and themethyl ester was hydrolyzed (m/z 283.0, (M−Bu+2H)⁺). The reactionmixture was diluted with ethyl acetate and the organic solution waswashed with 1N HCl, water, brine, and dried over Na₂SO₄. Afterfiltration, the filtrate was concentrated to yield 300 mg of crudematerial. The residue was stirred with a solution of MeOH (2 mL) in 4 NHCl-dioxane solution for 2 h to form the methyl ester. The volatileswere removed in-vacuo to yield 268 mg of the desired product. LC-MS:253.2 (M+H)⁺.

Example 272-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-5, and by thefollowing microwave mediated amine/aryl coupling procedure:

A mixture of2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride (5 mg, 0.00002 mol), 2-chloro-5-(trifluoromethyl)pyridine(6 mg, 0.00003 mol), and triethylamine (20 μL, 0.0001 mol) inN-methylpyrrolidinone (800 μL, 0.008 mol) was microwave irradiated at180° C. for 10 min. After cooling, it was purified by prep.-HPLC toafford 1.7 mg of the desired product. LC-MS: 398.3 (M+H)⁺.

Example 286-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 355.3 (M+H)⁺.

Example 292-(trans-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-5, and by thefollowing microwave mediated amine/aryl coupling procedure:

A mixture of2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride (35 mg, 0.00012 mol), 2-bromo-6-methoxypyridine (34 mg,0.00018 mol), triethylamine (200 μL, 0.001 mol), and copper(I) iodide(28 mg, 0.00014 mol) in N-methylpyrrolidinone (1.0 mL, 0.010 mol) wasmicrowave irradiated at 180° C. for 20 min. After allowing the reactionmixture to cool to rt the crude mixture was purified by prep.-HPLC toafford 8.3 mg of the desired product. LC-MS: 360.3 (M+H)⁺.

Example 302-(trans-4-Hydroxycyclohexyl)-7-(6-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 344.3 (M+H)⁺.

Example 312-(trans-4-Hydroxycylohexyl)-7-(5-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 344.3 (M+H)⁺.

Example 327-(5-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 348.3 (M+H)⁺.

Example 332-(trans-4-Hydroxycyclohexyl)-7-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 398.3 (M+H)⁺.

Example 34(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by chiral separation of example 27. PrepChiral LC conditions: Column: ChiralPak IA, 20×250 mm, 5 μm (ChiralTechnologies; Detection: 220 nm; Retention time: t=11.25 min for peak 1;t=19.21 min for peak 2). Example 34 corresponds to peak 2. LC-MS: 398.3(M+H)⁺.

Example 35(5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by chiral separation of example 34. Thiscompound corresponded to peak 1 of the chiral column. LC-MS: 398.3(M+H)⁺.

Example 367-(6-Fluoropyridin-2-yd)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 348.3 (M+H)⁺.

Example 372-(trans-4-Hydroxycyclohexyl)-7-(3-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 344.2 (M+H)⁺.

Example 382-(trans-4-Hydroxycyclohexyl)-7-(4-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 360.3 (M+H)⁺.

Example 392-(trans-4-Hydroxycyclohexyl)-7-pyridin-2-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 330.3 (M+H)⁺.

Example 40 (5R)-2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 17 followed by separation of theenantiomers using a chiral column. (Prep

Chiral LC conditions: Column: ChiralCel OD-H, 20×250 mm, 5 μm (ChiralTechnologies, Inc.); Mobile phase: 60% Ethanol/40% Hexanes; Flow rate: 8mL/min.; Detection: 220 nm; Retention time: t=8.66 min for peak 1;t=11.40 min for peak 2). This compound corresponded to peak 1. LC-MS:313.3 (M+H)⁺.

Example 41 (5S)-2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 40. This compound corresponded topeak 2 of the chiral column. LC-MS: 313.3 (M+H)⁺.

Example 427-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 432.2 (M+H)⁺.

Example 434-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 17, with the exception thatNaO-(t-Bu) was replaced by K₂CO₃. LC-MS: 354.2 (M+H)⁺.

Example 442-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-5, and by thefollowing microwave mediated amine/aryl coupling procedure:

A mixture of2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride (25 mg, 0.000086 mol), 1-bromo-4-(trifluoromethyl)benzene(29 mg, 0.00013 mol), sodium tert-butoxide (28 mg, 0.00029 mol),palladium acetate (0.6 mg, 0.000002 mol), and2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000002 mol) in 1,4-dioxane(1.0 mL, 0.013 mol) was heated at 100° C. with stirring for 16 h. LCMSindicated that most of the desired product was oxidized to the ketone sothe crude reaction mixture was cooled to −10° C. and 1.0 M ofL-selectride® in tetrahydrofuran (0.2 mL) was added and the mixture wasstirred for 20 min. LCMS indicated that the ketone was converted to thealcohol. The crude mixture was purified by prep.-HPLC to afford 5.2 mgof the desired product. LC-MS: 397.2 (M+H)⁺.

Example 453-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 43. LC-MS: 372.2 (M+H)⁺.

Example 464-(2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 43. LC-MS: 338.3 (M+H)⁺.

Example 474-(2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)-3-fluorobenzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 43. LC-MS: 356.3 (M+H)⁺.

Example 482-(trans-4-Hydroxycyclohexyl)-7-(piperidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-5, and by thefollowing urea coupling procedure.

Step 1. 4-nitrophenyl2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate

A mixture of2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride (0.30 g, 0.0010 mol), p-nitrophenyl chloroformate (0.25 g,0.0012 mol), and N,N-diisopropylethylamine (540 μL, 0.0031 mol) inmethylene chloride (4 mL, 0.06 mol) was stirred at rt for 16 h. Thecrude reaction mixture was purified by flash column chromatography toafford 120 mg of the desired product.

Step 2.2-(trans-4-hydroxycyclohexyl)-7-(piperidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one

To a solution of 4-nitrophenyl2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate(30 mg, 0.00007 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) was addedN,N-diisopropylethylamine (25.0 μL, 0.000144 mol) and piperidine (10 μL,0.0001 mol). After stirring at rt for 16 h, the crude reaction mixturewas purified by prep.-HPLC to afford the desired product. LC-MS: 364.3(M+H)⁺.

Example 492-(trans-4-Hydroxycyclohexyl)-7-(pyrrolidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 350.3 (M+H)⁺.

Example 502-(trans-4-Hydroxycyclohexyl)-7-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 438.3 (M+H)⁺.

Example 512-(trans-4-Hydroxycyclohexyl)-7-[(4-phenylpiperidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 440.3 (M+H)⁺.

Example 522-(trans-4-Hydroxycyclohexyl)-7-[(4-phenylpiperazin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 441.2 (M+H)⁺.

Example 537-{[4-(2-Fluorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 459.2 (M+H)⁺.

Example 542-(trans-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 509.2 (M+H)⁺.

Example 55 2-Cyclohexyl-7-isonicotinoyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-5, followed bythe following acylation procedure:

A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride(15 mg, 0.000055 mol), isonicotinoyl chloride hydrochloride (12 mg,0.000066 mol), and triethylamine (27 μL, 0.00019 mol) in acetonitrile(0.5 mL, 0.01 mol) was stirred at rt for 2 h. The crude reaction mixturewas purified by prep.-HPLC to afford 18 mg of the desired product.LC-MS: 342.3 (M+H)⁺.

Example 56 7-Benzoyl-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 55. LC-MS: 341.3 (M+H)⁺.

Example 572-Cyclohexyl-7-(pyridin-3-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 55. LC-MS: 342.3 (M+H)⁺.

Example 597-Benzoyl-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 55. LC-MS: 357.2 (M+H)⁺.

Example 61 Isopropyl{4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

Step 1.7-(4-Aminophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of2-(trans-4-hydroxycyclohexyl)-7-(4-nitrophenyl)-2,7-diazaspiro[4.5]decan-1-one(0.13 g, 0.00028 mol, prepared by using a procedure that was analogousto that described for the synthesis of example 43), 10% PdC (activated)in methanol (5 mL, 0.1 mol) was stirred under a H₂ atmosphere (balloon)for 1.5 hour. The catalyst was filtered and the filtrate wasconcentrated in-vacuo to afford the desired product in quantitativeyield. LC-MS: 344.3 (M+H)⁺.

Step 2. isopropyl{-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

A mixture of7-(4-aminophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(20 mg, 0.00006 mol), isopropyl chloroformate (11 mg, 0.000087 mol), andtriethylamine (20 μL, 0.0002 mol) in methylene chloride (300 μL, 0.005mol) was stirred at rt for 2 h. The crude reaction mixture was purifiedby prep.-HPLC to afford 17.4 mg of the desired product. LC-MS: 430.3(M+H)⁺.

Example 62 Prop-2-yn-1-yl{4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 426.3 (M+H)⁺.

Example 63Methyl{4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 402.2 (M+H)⁺.

Example 64N-{4-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 386.3 (M+H)⁺.

Example 65N-{4-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-phenyl}-cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 412.3 (M+H)⁺.

Example 66 Isopropyl{3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 448.3 (M+H)⁺.

Example 67 Prop-2-yn-1-yl{3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 444.3 (M+H)⁺.

Example 68 Methyl{3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]de-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 420.3 (M+H)⁺.

Example 69N-{3-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 430.3 (M+H)⁺.

Example 707-(4-Chloropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 365.3 (M+H)⁺.

Example 712-Cyclohexyl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 382.2 (M+H)⁺.

Example 72 2-Cyclohexyl-7-pyridin-2-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 314.3 (M+H)⁺.

Example 737-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 416.2 (M+H)⁺.

Example 742-Cyclohexyl-7-(piperidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures that were analogous tothose described for the synthesis of example 1, steps 1-5, and by thefollowing urea coupling procedure:

To a solution of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-onehydrochloride (20 mg, 0.00007 mol) in methylene chloride (0.5 mL, 0.008mol) was added N,N-diisopropylethylamine (14.0 μL, 0.0000806 mol) andthe solution was stirred at rt for 5 min. prior to the addition ofN,N-carbonyldiimidazole (24 mg, 0.00015 mol). After stirring thereaction mixture at rt for 3 h, piperidine (6.2 mg, 0.00007 mol) wasadded and stirring was continued for 12 h. To drive the reaction tocompletion the mixture was heated at 170° C. under microwave irradiationfor 1 h. The crude mixture was purified by prep.-HPLC to afford thedesired product. LC-MS: 348.2 (M+H)⁺.

Example 752-Cyclohexyl-7-(pyrrolidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 74. LC-MS: 334.2 (M+H)⁺.

Example 762-Cyclohexyl-7-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 74. LC-MS: 422.2 (M+H)⁺.

Example 772-Cyclohexyl-7-[(4-phenylpiperidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 74. LC-MS: 424.2 (M+H)⁺.

Example 782-Cyclohexyl-7-[(4-phenylpiperazin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 74. LC-MS: 425.2 (M+H)⁺.

Example 792-Cyclohexyl-7-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 74. LC-MS: 443.2 (M+H)⁺.

Example 802-Cyclohexyl-7-({4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 74. LC-MS: 493.2 (M+H)⁺.

Example 832-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 355.2 (M+H)⁺.

Example 847-(5-Chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 364.2/366.2 (M+H)⁺.

Example 857-(3,5-Dichloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 398.2/400.2/402.2(M+H)⁺.

Example 862-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 398.2 (M+H)⁺.

Example 872-(trans-4-Hydroxycyclohexyl)-7-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 412.3 (M+H)⁺.

Example 88 Methyl6-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 388.2 (M+H)⁺.

Example 892-(trans-4-Hydroxycyclohexyl)-7-isoquinolin-1-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 380.3 (M+H)⁺.

Example 902-(trans-4-Hydroxycyclohexyl)-7-quinolin-2-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 27. LC-MS: 380.2 (M+H)⁺.

Example 91N-{3-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 61. LC-MS: 404.3 (M+H)⁺.

Example 92(5S)-2-(2-Chlorophenyl)-7-(3,5-dichloropyridin-2-yn)-2,7-diazaspiro[4.5]decan-1-one

Step 1. 1-tert-butyl 3-ethyl3-(2-chloroethyl)piperidine-1,3-dicarboxylate

Lithium diisopropylamide (1.8 M in THF, 3.9 mL) was slowly added to asolution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (1.50 g,0.00583 mol) in tetrahydrofuran (20 mL, 0.2 mol) at −78° C. and themixture was stirred for about 1 hour during which the temperature wasallowed to rise to about −50° C. 1-Bromo-2-chloro-ethane (0.75 mL,0.0082 mol) was slowly added to the mixture and then the resultingmixture was allowed to warm to rt (room temperature). After stirring for2 h, the reaction mixture was quenched with saturated NH₄Cl andextracted with ethyl ether twice. The combined organic layers were driedand concentrated in-vacuo to afford the crude product, which waspurified by CombiFlash eluting with hexane/EtOAc (max. EA 20%).

Step 2. tert-butyl(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylateand tert-butyl(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate

Lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 2.5 mL) wasslowly added to a solution of o-chloroaniline (0.14 g, 0.0011 mol) intetrahydrofuran (4.0 mL, 0.049 mol) at −78° C. and stirred for 30 min.To this mixture was added a solution of 1-tert-butyl 3-ethyl3-(2-chloroethyl)piperidine-1,3-dicarboxylate (0.320 g, 0.00100 mol) inTHF (0.5 mL) and the resultant mixture was stirred for additional 18 h.The reaction mixture was quenched by an addition of methanol (2 mL) andthe solvent was removed in-vacuo to afford the racemic product, whichwas purified by CombiFlash (12 g column, eluting with hexane/EtOAc withmax. EtOAc 30%) to afford the desired racemate (0.26 g, 72%). LC-MS:309.1 (M+H−t-Bu (56)).⁺ The pure enantiomers were separated by chiralHPLC (Chiralcel OD-H column, 30×250 mm, 5 micron particle size fromChiral Technologies, Inc. Item number 14475; Mobile phase: Isocratic,30% ethanol, 70% hexanes; Flow Rate: 26 mL/min). The shorter retentiontime peak was found to be the R-enantiomer and the longer retention timepeak was found to be the S-enantiomer (the S-enantiomer was found to bemore active).

Step 3. (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride

Hydrogen chloride (4.0 M in 1,4-dioxane, 2.0 mL) was added to a solutionof tert-butyl(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate(0.103 g, 0.000283 mol) in ethyl acetate (0.5 mL) and the mixture wasstirred for 2 h. Then the solvent was removed in-vacuo to afford thedesired product. LC-MS: 265.2 (M+H).⁺

Step 4.(5S)-2-(2-chlorophenyl)-7-(3,5-dichloropyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride (18.2 mg, 0.0000604 mol), 2,3,5-trichloropyridine (16 mg,0.000091 mol) and triethylamine (0.025 mL, 0.00018 mol) inN,N-dimethylformamide (0.4 mL, 0.005 mol) was irradiated with microwavesto heat the mixture to 180° C. for 20 min. The crude product waspurified by prep-HPLC to afford the desired product. LC-MS:410.1/412.1/414.0 (M+H)⁺.

Example 932-(2-Chlorophenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

A mixture of 2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one (16.0 mg,0.0000604 mol, which was prepared by using a procedure that wasanalogous to that used for the synthesis of example 92, steps 1-4),2-chloro-5-(trifluoromethyl)pyridine (13 mg, 0.000072 mol) andN,N-diisopropylethylamine (0.032 mL, 0.00018 mol) inN-methylpyrrolidinone (0.4 mL, 0.005 mol) was irradiated with microwavesto heat the reaction mixture to 180° C. for 20 min. The crude productwas purified by prep-HPLC to afford the desired product. LC-MS:410.2/412.2 (M+H)⁺.

Example 942-(2-Chlorophenyl)-7-(3-chloropyrazin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 377.1/379.1 (M+H)⁺.

Example 952-(2-Chlorophenyl)-7-(3-chloropyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 376.1/378.1 (M+H)⁺.

Example 962-[(5S)-2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 92. LC-MS: 367.2/369.1 (M+H)⁺.

Example 97(5S)-2-(2-Chlorophenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 92. LC-MS: 410.1/412.1 (M+H)⁺.

Example 986-[(5S)-2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 92. LC-MS: 367.2/369.1 (M+H)⁺.

Example 99Methyl{6-[(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

Step 1.(5S)-7-(5-aminopyridin-2-yl)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride (40.0 mg, 0.000133 mol, prepared by using a procedureanalogous to that used for the synthesis of example 92, steps 1-3),2-chloro-5-nitropyridine (23 mg, 0.00015 mol), and potassium carbonate(55 mg, 0.00040 mol) in N,N-dimethylformamide (1.0 mL, 0.013 mol) wasstirred at 120° C. for 1.5 hours. After cooling the reaction mixture toambient temperature the solid was filtered off and the filtrate wasconcentrated in-vacuo to afford the desired product. LC-MS: 387.1(M+H)⁺. The resulting residue was dissolved in methanol and to thissolution was added platinum [5 wt. % (dry basis) on activated carbon,wet, Degussa type F101, RAW (Aldrich # 330159), 15 mg] under anatmosphere of H₂ (g) at rt for 2 h. The catalyst was filtered off fromthe mixture and the filtrate was concentrated in-vacuo to afford theproduct in quantitative yield. LC-MS: 357.1 (M+H)⁺.

Step 2.Methyl{6-[(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of(5S)-7-(5-aminopyridin-2-yl)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one(18.5 mg, 0.0000478 mol) and pyridine (13 μL, 0.00016 mol) in methylenechloride (1.0 mL, 0.016 mol) and the mixture was stirred for 0.5 h atrt. The volatiles were removed in-vacuo and the crude product waspurified by prep-HPLC. LC-MS: 415.1/417.1 (M+H)⁺.

Example 100 Ethyl{6-[(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 99. LC-MS: 429.1 (M+H)⁺.

Example 101 Propyl{6-[(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 99. LC-MS: 443.1 (M+H)⁺.

Example 1026-[2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylnicotinamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 399.2 (M+H)⁺.

Example 1036-[2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-ethylnicotinamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 413.2 (M+H)⁺.

Example 104(5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-oneand(5S)-2-(Tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

Racemic2-(tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one(9.0 mg, 0.000023 mol, the racemic mixture was prepared by usingprocedures analogous to those described for the synthesis of example 93)was purified by chiral column (see Example 92 for column conditions) togive the pure two enantiomers. The shorter retention time peak was foundto be the R-enantiomer and the longer retention time peak was found tobe the S-enantiomer. The S-enantiomer was found to be more active.LC-MS: 384.2 (M+H)⁺.

Example 105Methyl{6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

Step 1.(5S)-7-(5-aminopyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one [90 mg,0.0004 mol, this compound was prepared by using procedures analogous tothose described for the synthesis of example 92, steps 1-3],2-chloro-5-nitropyridine (69 mg, 0.00044 mol), and potassium carbonate(160 mg, 0.0012 mol) in N,N-dimethylformamide (2 mL, 0.02 mol) wasstirred at 120° C. for 1.5 hours. After cooling the reaction mixture toambient temperature, the solid was filtered off and the filtrate wasconcentrated in-vacuo to afford the desired product. LC-MS: 361.2(M+H)⁺. The resulting residue was dissolved in methanol and to thissolution was added 10% Pd on carbon and the reaction vessel was placedunder a H₂ (g) atmosphere and stirred at rt for 1.5 h. The catalyst wasfiltered off from the mixture and the filtrate was concentrated toafford the desired product in quantitative yield and was used in thenext step without further purification. LC-MS: 331.2 (M+H)⁺.

Step 2.Methyl{6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of(5S)-7-(5-aminopyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one(15.8 mg, 0.0000478 mol), N,N-diisopropylethylamine (27 μL, 0.00016 mol)and methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirredfor 1 h. The volatiles were removed in-vacuo and the crude product waspurified by prep-HPLC. LC-MS: 389.2 (M+H)⁺.

Example 106 Ethyl{6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 403.3 (M+H)⁺.

Example 107 Propyl{6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 417.3 (M+H)⁺.

Example 108 Isopropyl{6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 417.3 (M+H)⁺.

Example 109 Isobutyl{6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 431.3 (M+H)⁺.

Example 110(5S)-7-(3-Chloropyrazin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one asdescribed in example 105. LC-MS: 351.1 (M+H)⁺.

Example 1113-[(5S)-1-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2-carbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one asdescribed in example 105. LC-MS: 342.2 (M+H)⁺.

Example 112(5S)-7-(3-Chloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decant-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one asdescribed in example 105. LC-MS: 350.2 (M+H)⁺.

Example 1132-[(5S)-1-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrite

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one asdescribed in example 105. LC-MS: 341.2 (M+H)⁺.

Example 114(5S)-2-(Tetrahydro-2H-pyran-4-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one asdescribed in example 105. LC-MS: 384.2 (M+H)⁺.

Example 115(5S)-7-(3,5-Dichloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 as described in example 105.LC-MS: 384.1 (M+H)⁺.

Example 116(5S)-7-(5-Chloropyridin-2-yd)-2-(tetrahydro-2H-pyran-4-yn)-2,7-diazaspiro[4.5]decan-1-one

A mixture of(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-onehydrochloride (29.4 mg, 0.000107 mol, this compound was prepared byusing procedures analogous to those described for the synthesis ofexample 92, steps 1-3), 5-chloro-2-fluoropyridine (17 mg, 0.000013 mol)and potassium carbonate (0.029 mL, 0.00032 mol) in N,N-dimethylformamide(0.6 mL, 0.008 mol) was heated at 120° C. for 5 h. The crude product waspurified by prep-HPLC to afford the desired product. LC-MS: 350.2(M+H)⁺.

Example 117Methyl{5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 423.1 (M+H)⁺.

Example 118 Ethyl{5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 437.2 (M+H)⁺.

Example 119 Propyl{5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 451.2 (M+H)⁺.

Example 120 Isopropyl{5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 451.2 (M+H)⁺.

Example 121 Isobutyl{5-chloro-6-[(5S)-b-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 465.2 (M+H)⁺.

Example 1223-Chloro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yd)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 374.1 (M+H)⁺.

Example 1236-[(5S)-1-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrite

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 341.2 (M+H)⁺.

Example 124(5S)-7-(3,5-Difluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 352.2 (M+H)⁺.

Example 125(5S)-7-Isoquinodin-1-yl-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 366.3 (M+H)⁺.

Example 126(5S)-7-quinolin-2-yl-2-(tetrahydro-2H-pyran-4-yn)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 366.2 (M+H)⁺.

Example 127Methyl{5-methyl-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 403.2 (M+H)⁺.

Example 128 Ethyl{5-methyl-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 417.2 (M+H)⁺.

Example 129 Propyl{5-methyl-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 431.2 (M+H)⁺.

Example 130 Methyl{3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 406.3 (M+H)⁺.

Example 131 Ethyl{3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 420.2 (M+H)⁺.

Example 132 Propyl{3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 434.2 (M+H)⁺.

Example 133 Isopropyl{3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 434.3 (M+H)⁺.

Example 134 Isobutyl{3-fluoro-4-[(5S)-b-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 448.3 (M+H)⁺.

Example 135Methyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 388.3 (M+H)⁺.

Example 136 Ethyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 402.2 (M+H)⁺.

Example 137 Propyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 416.3 (M+H)⁺.

Example 138 Isopropyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 416.2 (M+H)⁺.

Example 139 Isobutyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 430.3 (M+H)⁺.

Example 140 Methylmethyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

Sodium hydride (1.6 mg, 0.000041 mol) was added to a solution ofmethyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate(8.0 mg, 0.000021 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) at rt.After stirring for 5 min., methyl iodide (2.6 μL, 0.000041 mol) wasadded and the reaction mixture was stirred for 1 h at rt. The crudeproduct was purified by prep-HPLC. LC-MS: 402.3 (M+H)⁺.

Example 1413-Fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 358.2 (M+H)⁺.

Example 1422-(1-Methylpiperidin-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 397.2 (M+H)⁺.

Example 143 Methyl4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}piperidine-1-carboxylate

Step 1.2-piperidin-4-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

A mixture of tert-butyl4-(1-oxo-2,7-diazaspiro[4.5]dec-2-yl)piperidine-1-carboxylate (36.0 mg,0.000107 mol, this compound was prepared by using a procedure that wasanalogous to that described for the synthesis of example 1, steps 1-4followed by Pd catalyzed hydrogenation to remove the Cbz protectinggroup), 2-chloro-5-(trifluoromethyl)pyridine (23 mg, 0.00013 mol) andN,N-diisopropylethylamine (0.056 mL, 0.00032 mol) inN-methylpyrrolidinone (0.8 mL, 0.008 mol) was irradiated with microwavesto heat the mixture to 180° C. for 20 min. The mixture was diluted withethyl acetate and washed with water and brine, dried over sodiumsulfate, filtered and concentrated to afford the desired Boc-protectedproduct. LC-MS: 483.2 (M+H)⁺. The residue was treated with 4 N HCl indioxane to afford the de-Boc product. LC-MS: 383.2 (M+H)⁺.

Step 2. Methyl4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}piperidine-1-carboxylate

Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of2-piperidin-4-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one(18.3 mg, 0.0000478 mol) and N,N-diisopropylethylamine (27 μL, 0.00016mol) in methylene chloride (1.0 mL, 0.016 mol); and the mixture wasstirred for 0.5 h. The volatiles were removed in-vacuo and the productwas purified by prep-HPLC. LC-MS: 441.2 (M+H)⁺.

Example 144N,N-Dimethyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}piperidine-1-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 143. LC-MS: 454.2 (M+H)⁺.

Example 1457-(3-Chloropyrazin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 394.2 (M+H)⁺.

Example 1467-(3-Chloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 393.2 (M+H)⁺.

Example 1477-(3,5-Dichloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 427.2 (M+H)⁺.

Example 1482-(2-Methylphenyl)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 391.2 (M+H)⁺.

Example 1497-(4-Chloropyrimidin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 357.2 (M+H)⁺.

Example 1507-(6-Chloro-7H-purin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 397.2 (M+H)⁺.

Example 1513-[2-(2-Methylphenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2-carbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 348.2 (M+H)⁺.

Example 1527-(6-Chloropyrazin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 357.2 (M+H)⁺.

Example 1537-(3-Chloropyrazin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 357.2 (M+H)⁺.

Example 1542-(2-Methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 390.2 (M+H)⁺.

Example 1552-Quinolin-5-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 427.2 (M+H)⁺.

Example 1562-Isoquinolin-5-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 427.2 (M+H)⁺.

Example 1572-(4-Bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 468.1/470.1 (M+H)⁺.

Example 1583-Methyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}benzonitrile

A mixture of2-(4-bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one(63.6 mg, 0.000136 mol), zinc cyanide (32 mg, 0.00027 mol), potassiumcarbonate (0.056 g, 0.00041 mol) and tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.000007 mol) in N,N-dimethylformamide (0.5 mL,0.006 mol) was stirred at 100° C. for 2 days. The reaction mixture wascooled to ambient temperature and purified by prep-HPLC (under pH 10) toafford the desired product. LC-MS: 415.2 (M+H)⁺.

Example 159N-(3-Methyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}phenyl)acetamide

To a solution of2-(4-bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one(38.1 mg, 0.0000814 mol), in 1,4-dioxane (0.5 mL, 0.006 mol) was added(1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.3 mg, 0.000016 mol),copper(I) iodide (1.6 mg, 0.0000081 mol), acetamide (9.6 mg, 0.00016mol), and potassium carbonate (23.6 mg, 0.000171 mol) and the mixturewas stirred at 100° C. overnight. The product was purified by prep-HPLC.LC-MS: 447.2 (M+H)⁺.

Example 160N-(3-Methyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}phenyl)methanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 159. LC-MS: 483.2 (M+H)⁺.

Example 1612-(3-Methylpyridin-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

Step 1. J-tert-butyl 3-ethyl3-[2-(tritylamino)ethyl]piperidine-1,3-dicarboxylate

Trietylamine (180 mg, 0.00068 mol) was added to a solution of1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.170g, 0.000568 mol, this was prepared by using procedures analogous to thatdescribed for the synthesis of example 1, steps 1-2) in1,2-dichloroethane (4.0 mL, 0.051 mol) and followed by sodiumtriacetoxyborohydride (0.36 g, 0.0017 mol) and the mixture was stirredovernight. The mixture was poured into pre-cooled water, and extractedwith ethyl acetate. The organic layer was separated, dried (NaSO₄), andconcentrated in-vacuo. The product was purified by CombiFlash elutingwith hexane/EtOAc (max EtOAc 20%). LC-MS: 543.3 (M+H)⁺; 243.2.

Step 2. 2,7-diazaspiro[4.5]decan-1-one

Trifluoroacetic acid (1.0 mL, 0.013 mol) was added to a solution of1-tert-butyl 3-ethyl3-[2-(tritylamino)ethyl]piperidine-1,3-dicarboxylate (0.10 g, 0.00018mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture wasstirred for 1 h at rt to remove the Boc and trityl groups. Then thesolvent was removed under vacuum and to the resultant residue was added1,4-dioxane (3.0 mL, 0.038 mol) followed by N,N-diisopropylethylamine(0.13 mL, 0.00074 mol) and the resultant mixture was stirred at 150° C.(microwave) for 1 h. The solvent from the mixture was removed undervacuum and the crude product was used in the next step without furtherpurification. LC-MS: 155.2 (M+H)⁺.

Step 3.7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

A mixture of 2,7-diazaspiro[4.5]decan-1-one (50.0 mg, 0.000324 mol),2-chloro-5-(trifluoromethyl)pyridine (71 mg, 0.00039 mol) andN,N-diisopropylethylamine (0.17 mL, 0.00097 mol) inN-methylpyrrolidinone (2 mL, 0.02 mol) was irradiated with microwaves at180° C. for 20 min. The product was purified by prep-HPLC. LC-MS: 300.2(M+H)⁺.

Step 4.2-(3-methylpyridin-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

To a solution of7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one (24.4mg, 0.0000814 mol) in 1,4-dioxane (0.5 mL, 0.006 mol) were added(1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.3 mg, 0.000016 mol),copper(I) iodide (1.6 mg, 0.0000081 mol), 4-bromo-3-methylpyridine (28mg, 0.00016 mol) and potassium carbonate (23.6 mg, 0.000171 mol); andthe mixture was stirred at 100° C. overnight. The product was purifiedby prep-HPLC. LC-MS: 391.2 (M+H)⁺.

Example 1622-(4-Methylpyridin-3-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

Step 1. J-tert-butyl 3-ethyl3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-1,3-dicarboxylate

4-Methylpyridin-3-amine (36.0 mg, 0.000333 mol) was added to a solutionof 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate(0.095 g, 0.00032 mol) in 1,2-dichloroethane (1.9 mL, 0.025 mol) andfollowed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol) and themixture was stirred for 24 h. The mixture was poured into pre-cooledwater, extracted with ethyl acetate. The organic layer was separated,dried and concentrated. The product was purified by CombiFlash usingCH₂Cl₂EtOAc (max EtOAc 50%). LC-MS: 392.3 (M+H)⁺.

Step 2. ethyl3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-3-carboxylatetrihydrochloride

Hydrogen chloride in 1,4-dioxane (4.0 M, 2.0 mL) was added to a solutionof 1-tert-butyl 3-ethyl3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-1,3-dicarboxylate(0.036 g, 0.000092 mol) in ethyl acetate (0.5 mL) and the mixture wasstirred for 2 h. Then the solvent was removed in-vacuo to afford theproduct. LC-MS: 292.3 (M+H)⁺.

Step 3.2-(4-methylpyridin-3-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

A mixture of ethyl3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-3-carboxylatetrihydrochloride (42.8 mg, 0.000107 mol),2-chloro-5-(trifluoromethyl)pyridine (23 mg, 0.00013 mol) andN,N-diisopropylethylamine (0.056 mL, 0.00032 mol) inN-methylpyrrolidinone (0.8 mL, 0.008 mol) was irradiated with microwavesto 180° C. for 20 min. Sodium hydride (30.0 mg) was then added to theabove solution and the mixture was stirred overnight. The product waspurified by prep-HPLC. LC-MS: 391.2 (M+H)⁺.

Example 1637-(3-Chloropyrazin-2-yl)-2-(1-methylpiperidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 364.1 (M+H)⁺.

Example 164 Methyl[4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 454.2 (M+H)⁺.

Example 165 Ethyl[4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 468.2 (M+H)⁺.

Example 166 Prop-2-yn-1-yl[4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 478.1 (M+H)⁺.

Example 167N-[4-[(5S)-2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 438.1 (M+H)⁺.

Example 168N-[4-[(5S)-2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]methanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 474.1 (M+H)⁺.

Example 169 Methylmethyl[4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 140. LC-MS: 468.1 (M+H)⁺.

Example 170 Prop-2-yn-1-yl{5-chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group. LC-MS: 461.1 (M+H)⁺.

Example 171Methyl{5-chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group. LC-MS: 437.1 (M+H)⁺.

Example 172 Ethyl{5-chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group. LC-MS: 451.1 (M+H)⁺.

Example 173N-{5-Chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group. LC-MS: 421.1 (M+H)⁺.

Example 174N-{5-Chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}methanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group. LC-MS: 457.2 (M+H)⁺.

Example 1754-{1-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 407.2 (M+H)⁺.

Example 1764-{1-Oxo-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 406.2 (M+H)⁺.

Example 1774-{7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 441.2 (M+H)⁺.

Example 1784-[7-(3,5-Dichloropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexanecarbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 407.2/409.2 (M+H)⁺.

Example 1794-[7-(6-Fluoropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexanecarbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 357.1 (M+H)⁺.

Example 180(5S)-7-(2-Fluoro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20mg, 0.00007 mol) which was prepared using procedures analogous to thosedescribed in the synthesis of example 472-a and followed by standardhydrogenation to remove the carbobenzyloxy (Cbz) protecting and,4-methyl-2-fluoro-1-iodobenzene (21 mg, 0.00009 mol), sodiumtert-butoxide (9.98 mg, 0.000104 mol),1,4,7,10,13,16-hexaoxacyclooctadecane (27.4 mg, 0.000104 mol),2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000003 mol),tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), intert-butyl alcohol (1.0 mL, 0.010 mol) was stirred at rt for 18. Thecrude product was purified by prep-HPLC to afford the desired product.LC-MS: 361.1 (M+H)⁺.

Example 181(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(4-methoxyphenyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 359.1 (M+H)⁺.

Example 182{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 368.1 (M+H)⁺.

Example 183(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethoxy)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 413.1 (M+H)⁺.

Example 184(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]-decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 397.1 (M+H)⁺.

Example 185(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethoxy)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 413.1 (M+H)⁺.

Example 186(5S)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 377.1 (M+H)⁺.

Example 187(5S)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 377.1 (M+H)⁺.

Example 188(5S)-7-(2-Chloro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20mg, 0.00007 mol) which was prepared using procedures analogous to thosedescribed in the synthesis of example 472-a and followed by standardhydrogenation to remove the carbobenzyloxy (Cbz) protecting group and2-chloro-1-iodo-4-methylbenzene (22.7 mg, 0.0000831 mol), potassiumcarbonate (20.1 mg, 0.000145 mol), copper(I) iodide (0.6 mg, 0.000003mol), and (1S,2S)-cyclohexane-1,2-diol (16.1 mg, 0.000138 mol) intert-butyl alcohol (1.0 mL, 0.010 mol) was heated at 100° C. for 18 h.The crude product was purified by prep-HPLC to afford the desiredproduct. LC-MS: 377.1 (M+H)⁺.

Example 1892-Fluoro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 372.1 (M+H)⁺.

Example 190(5S)-7-(2,5-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 397.2/399.2 (M+H)⁺.

Example 191(5S)-7-(2,3-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 397.2/399.2 (M+H)⁺.

Example 192(5S)-7-(3,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 365.1 (M+H)⁺.

Example 193(5S)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 377.1 (M+H)⁺.

Example 194(5S)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]-decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 377.1 (M+H)⁺.

Example 195(5S)-7-(2,6-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 397.2/399.2 (M+H)⁺.

Example 1963-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 188. LC-MS: 354.2 (M+H)⁺.

Example 197(5S)-7-(2-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 347.1 (M+H)⁺.

Example 198(5S)-7-(2-Chlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 363.1 (M+H)⁺.

Example 199(5S)-7-(4-Chloro-2-fluorophenyl)-2-(trans-4-hydroxycylohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 381.1 (M+H)⁺.

Example 200(5S)-7-(2,4-Difluorophenyl)-2-(trans-4-hydroxycylohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 365.1 (M+H)⁺.

Example 201(5S)-7-(3-Chloro-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 381.1 (M+H)⁺.

Example 202(trans-4-{1-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexyl)acetonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 421.1 (M+H)⁺.

Example 203(trans-4-{1-Oxo-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexyl)acetonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 420.1 (M+H)⁺.

Example 204(trans-4-{7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexyl)acetonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 455.1 (M+H)⁺.

Example 205{trans-4-[7-(3,5-Dichloropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexyl}acetonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 421.1 (M+H)⁺.

Example 206{trans-4-[7-(6-Fluoropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexyl}acetonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 371.1 (M+H)⁺.

Example 207(5S)-2-(trans-4-Hydroxycylohexyl)-7-(3,5,6-trifluoropyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 384.1 (M+H)⁺.

Example 208(5S)-7-(4,6-Dimethoxypyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 391.1 (M+H)⁺.

Example 209(5S)-7-[4-Fluoro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 417.1 (M+H)⁺.

Example 210(5S)-7-(2,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 365.1 (M+H)⁺.

Example 211(5S)-7-[2-(Difluoromethoxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 395.1 (M+H)⁺.

Example 212(5S)-7-(4-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 349.1 (M+H)⁺.

Example 213(5S)-7-[4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 433.1 (M+H)⁺.

Example 214(5S)-2-(trans-4-Hydroxycyclohexyl)-7-quinazolin-4-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 381.1 (M+H)⁺.

Example 215(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 360.1 (M+H)⁺.

Example 216(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[6-(methylamino)-9H-purin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 400.1 (M+H)⁺.

Example 218-a7-{[4-(2-Chlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 475.1 (M+H)⁺.

Example 218-b2-(trans-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)quinolin-4-yl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 560.1 (M+H)⁺.

Example 2192-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 510.1 (M+H)⁺.

Example 2202-(trans-4-Hydroxycyclohexyl)-7-{[4-(2-methylphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 455.1 (M+H)⁺.

Example 2217-{[4-(3,4-Dichlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 509.1 (M+H)⁺.

Example 2222-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 509.1 (M+H)⁺.

Example 2237-[(4-Biphenyl-4-ylpiperazin-1-yl)carbonyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 517.1 (M+H)⁺.

Example 2242-(trans-4-Hydroxycyclohexyl)-7-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 510.1 (M+H)⁺.

Example 2252-(trans-4-Hydroxycyclohexyl)-7-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 471.1 (M+H)⁺.

Example 2262-(trans-4-Hydroxycyclohexyl)-7-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 442.1 (M+H)⁺.

Example 2277-{[4-(4-Chlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 475.1 (M+H)⁺.

Example 2287-{[4-(2-Ethoxyphenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 485.1 (M+H)⁺.

Example 2292-(trans-4-Hydroxycyclohexyl)-7-{[4-(3-methoxyphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 471.1 (M+H)⁺.

Example 2302-(trans-4-Hydroxycyclohexyl)-7-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 455.1 (M+H)⁺.

Example 2317-{[4-(3-Chlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 475.1 (M+H)⁺.

Example 2322-(trans-4-Hydroxycyclohexyl)-7-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 471.1 (M+H)⁺.

Example 2334-(4-{[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]carbonyl}piperazin-1-yl)benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 466.1 (M+H)⁺.

Example 2347-{[4-(3,5-Dichloropyridin-4-yl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 510.1 (M+H)⁺.

Example 235(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(1,3-thiazol-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 336.2 (M+H)⁺.

Example 2362-(trans-4-Hydroxycyclohexyl)-7-({4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 48. LC-MS: 509.1 (M+H)⁺.

Example 2377-(3,5-Dichloropyridin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 451.1 (M+H)⁺.

Example 238 Propyl{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MS: 500.2(M+H)⁺.

Example 2392-(4-Hydroxy-1-adamantyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 450.2 (M+H)⁺.

Example 240 Ethyl{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MS: 486.2(M+H)⁺.

Example 2417-(3,5-Difluoropyridin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 418.2 (M+H)⁺.

Example 2423-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 424.2 (M+H)⁺.

Example 2432-[2-(4-Hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 407.2 (M+H)⁺.

Example 2444-[2-(4-Hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 406.2 (M+H)⁺.

Example 245N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MS: 482.2(M+H)⁺.

Example 2462-(4-Hydroxy-1-adamantyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 450.2 (M+H)⁺.

Example 2477-(5-Ethylpyrimidin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 411.2 (M+H)⁺.

Example 2487-(3-Fluoropyridin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 400.2 (M+H)⁺.

Example 249N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MS: 456.2(M+H)⁺.

Example 250N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MS: 470.2(M+H)⁺.

Example 251N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting from2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MS: 492.2(M+H)⁺.

Example 252(5S)-7-(2,3-Difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 365.2 (M+H)⁺.

Example 253(5S)-7-(3-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 347.3 (M+H)⁺.

Example 254(5S)-7-(2-Chloro-3-fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 381.2 (M+H)⁺.

Example 255(5S)-7-(4-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 347.2 (M+H)⁺.

Example 256(5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

3-Chloropropyl chloridocarbonate (15.1 μL, 0.000125 mol) was added to amixture of(5S)-7-(5-amino-3-chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(37.89 mg, 0.0001000 mol, this compound was prepared by using proceduresanalogous to those described for the synthesis of example 105, step 1starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one) and4-dimethylaminopyridine (18.3 mg, 0.000150 mol) in DMF (1.00 mL). Afterstirring the mixture for 1 h, 1.0000 M of potassium tert-butoxide intetrahydrofuran (0.375 mL) was added and the resultant mixture wasstirred at rt for 2 h. The mixture was diluted with methanol (0.8 mL)and was adjusted to pH=2.0 with TFA. The resulting solution was purifiedby prep.-HPLC to give the desired product. LC-MS: 463.1 (M+H)⁺.

Example 257(5S)-7-(3,4′-Bipyridin-6-yd)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

Sodium carbonate (10.6 mg, 0.000100 mol) in water (0.10 mL) was added toa mixture of 2-5(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20.4 mg,0.0000500 mol) which was prepared by using a procedure that wasanalogous to the one described for the synthesis of example 93 startingfrom (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-onein NMP (0.25 mL), 4-pyridinylboronic acid (9.22 mg, 0.0000750 mol) andtetrakis(triphenylphosphine) palladium(0) (1.7 mg, 0.0000015 mol) intoluene (200.0 μL, 0.001878 mol) and ethanol (100.000 μL, 1.71267E-3mol). The resulting mixture was heated at 120° C. for 20 min. Themixture was filtered and the filtrate was diluted with methanol andadjusted to pH=2 with TFA. The resulting solution was purified byprep.-HPLC to give the desired product. LC-MS: 407.2 (M+H)⁺.

Example 258(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(6′-methoxy-3,3′-bipyridin-6-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 437.3 (M+H)⁺.

Example 2594-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-N,N-dimethylbenzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 477.3 (M+H)⁺.

Example 2604-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 449.3 (M+H)⁺.

Example 261N-Cyclopropyl-4-{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 489.3 (M+H)⁺.

Example 262N-(4-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}phenyl)acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 463.3 (M+H)⁺.

Example 263(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(4-methoxyphenyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 436.3 (M+H)⁺.

Example 264(5S)-7-[5-(4-Fluorophenyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 424.2 (M+H)⁺.

Example 265(5S)-7-(3,3′-Bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 407.3 (M+H)⁺.

Example 266(5S)-7-(6′-Fluoro-3,3′-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 425.3 (M+H)⁺.

Example 267(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrimidin-5-ylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 408.3 (M+H)⁺.

Example 2683-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 449.3 (M+H)⁺.

Example 269N-(3-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}phenyl)acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 463.3 (M+H)⁺.

Example 270(5S)-7-[5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 425.3 (M+H)⁺.

Example 271(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 410.3 (M+H)⁺.

Example 2724-{2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}-N,N-dimethylbenzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 478.2 (M+H)⁺.

Example 273(5S)-2-(trans-4-Methoxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one whichwas prepared by treating of (S)-benzyl2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylatewith NaH and MeI in DMF, followed by Pd catalyzed Cbz deprotection.LC-MS: 412.2 (M+H)⁺.

Example 274N-Cyclopropyl-4-{2-[(5S)-2-(trans-4-hydroxycyclohexyl)-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 490.2 (M+H)⁺.

Example 275(5S)-7-(5-Chloro-3,3′-bipyridin-6-yd)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 441.2 (M+H)⁺.

Example 276(5S)-7-(5-Bromopyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 409.1/411.1 (M+H)⁺.

Example 277(5S)-7-[3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 444.2 (M+H)⁺.

Example 2784-{2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 450.2 (M+H)⁺.

Example 279(5S)-7-(3,5-Difluoropyridin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-oneError! Objects Cannot be Created from Editing Field Codes

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 273. LC-MS: 380.2 (M+H)⁺.

Example 280(5S)-7-(5-Chloro-3,4′-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 441.2 (M+H)⁺.

Example 281(5S)-7-(5-Ethylpyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-oneError! Objects Cannot be Created from Editing Field Codes

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 273. LC-MS: 373.3 (M+H)⁺.

Example 282 tert-Butyl5-chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 545.3 (M+H)⁺.

Example 283(5S)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 349.2 (M+H)⁺.

Example 284(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 414.3 (M+H)⁺.

Example 285(5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 432.2 (M+H)⁺.

Example 286(5S)-7-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 430.3 (M+H)⁺.

Example 287(5S)-7-[3-Chloro-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 447.3 (M+H)⁺.

Example 288(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxopyrrolidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 412.2 (M+H)⁺.

Example 289(5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 449.1 (M+H)⁺.

Example 290(5S)-7-(2-Fluoro-4-pyrrolidin-1-ylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of 1,4-diiodobutane (13.5 μL, 0.000100 mol),(5S)-7-(4-amino-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(28.9 mg, 0.0000800 mol, this compound was prepared by using proceduresanalogous to that described for the synthesis of example 105, step 1starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one) and4-dimethylaminopyridine (14.7 mg, 0.000120 mol) in DMF (1.00 mL), andpotassium iodide (1.5 mg, 0.0000090 mol) was heated at 110° C. bymicrowave for 15 min. The mixture was diluted with methanol (0.8 mL) andwas adjusted to be acidic with TFA (the pH was about 2.0). The resultingsolution was purified by prep-HPLC to give the desired product. LC-MS:416.2 (M+H)⁺.

Example 291(5S)-7-(3-Chloro-5-pyrrolidin-1-ylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 290. LC-MS: 433.2 (M+H)⁺.

Example 292(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrrolidin-1-ylpyridin-2-yl)-2,7-diazaspiro[4.5]de-an-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 290. LC-MS: 399.2 (M+H)⁺.

Example 293(5S)-7-[2-Fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-(trans-4-hydroxy-cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 444.3 (M+H)⁺.

Example 294(5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazinan-3-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 446.3 (M+H)⁺.

Example 295(5S)-2-(trans-4-hydroxycyclohexyl)-7-[4-(2-oxopiperidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 426.3 (M+H)⁺.

Example 296(5S)-7-(1,3-Benzothiazol-2-yn)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 386.2 (M+H)⁺.

Example 2972-[(5S)-2-(trans-4-Methoxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 273. LC-MS: 369.2 (M+H)⁺.

Example 298(5S)-2-(trans-4-Methoxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 273. LC-MS: 412.2 (M+H)⁺.

Example 299(5S)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 273. LC-MS: 363.2 (M+H)⁺.

Example 300(5S)-7-{3-Chloro-5-[4-(trifluoromethoxy)phenyl]pyridin-2-yl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 524.2 (M+H)⁺.

Example 301(5S)-7-(2-Chloro-9H-purin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 405.2 (M+H)⁺.

Example 302(5S)-7-(4-Amino-5-fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 364.2 (M+H)⁺.

Example 303N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 430.3 (M+H)⁺.

Example 304N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclobutanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 444.3 (M+H)⁺.

Example 305N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopentanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 458.3 (M+H)⁺.

Example 306N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclohexanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 472.3 (M+H)⁺.

Example 307 Ethyl{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 434.3 (M+H)⁺.

Example 308 Propyl{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 448.3 (M+H)⁺.

Example 309 Isobutyl{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 462.3 (M+H)⁺.

Example 310N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 418.3 (M+H)⁺.

Example 311N-{₃-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-2-methylpropanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 432.3 (M+H)⁺.

Example 312N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 440.2 (M+H)⁺.

Example 313N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}ethanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 454.2 (M+H)⁺.

Example 314(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 398.2 (M+H)⁺.

Example 315 Ethyl[4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 484.3 (M+H)⁺.

Example 316 Methyl[4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 470.2 (M+H)⁺.

Example 317 Propyl[4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 498.3 (M+H)⁺.

Example 318 Isobutyl[4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 512.3 (M+H)⁺.

Example 319 Isopropyl[4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 498.3 (M+H)⁺.

Example 320N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 480.3 (M+H)⁺.

Example 321N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 494.3 (M+H)⁺.

Example 322N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]cyclopentanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 508.3 (M+H)⁺.

Example 323N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]methanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 490.2 (M+H)⁺.

Example 324N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 454.3 (M+H)⁺.

Example 325N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]propanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 468.3 (M+H)⁺.

Example 326N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]-2-methylpropanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 482.3 (M+H)⁺.

Example 327(5S)-7-[2-Fluoro-4-(pyridin-2-yloxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 440.3 (M+H)⁺.

Example 328Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 403.3 (M+H)⁺.

Example 329 Ethyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 417.3 (M+H)⁺.

Example 330 Propyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 431.3 (M+H)⁺.

Example 331 Isobutyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 445.3 (M+H)⁺.

Example 332 Isopropyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 431.3 (M+H)⁺.

Example 333N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 413.3 (M+H)⁺.

Example 334N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclobutanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 427.3 (M+H)⁺.

Example 335N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclopentanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 441.3 (M+H)⁺.

Example 336N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 387.3 (M+H)⁺.

Example 337N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}propanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 401.3 (M+H)⁺.

Example 338N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-2-methylpropanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 415.3 (M+H)⁺.

Example 339N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclohexanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 455.3 (M+H)⁺.

Example 340Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 417.1 (M+H)⁺.

Example 341 Ethyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 431.2 (M+H)⁺.

Example 342 Propyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 445.1 (M+H)⁺.

Example 343 Methyl{3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 427.2 (M+H)⁺.

Example 344 Ethyl{3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 441.3 (M+H)⁺.

Example 345 Propyl{3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 455.3 (M+H)⁺.

Example 346 Isobutyl{3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 469.3 (M+H)⁺.

Example 347 Isopropyl{3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 455.3 (M+H)⁺.

Example 348N-[3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl]cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 437.3 (M+H)⁺.

Example 349N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclobutanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 451.3 (M+H)⁺.

Example 350N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopentanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 465.3 (M+H)⁺.

Example 351N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 411.3 (M+H)⁺.

Example 352N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 425.3 (M+H)⁺.

Example 353N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-2-methylpropanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 439.3 (M+H)⁺.

Example 354N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclohexanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 479.3 (M+H)⁺.

Example 355Methyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 416.3 (M+H)⁺.

Example 356 Ethyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 430.3 (M+H)⁺.

Example 357 Propyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 444.3 (M+H)⁺.

Example 358 Isobutyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 458.3 (M+H)⁺.

Example 359 Isopropyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 444.3 (M+H)⁺.

Example 360N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclopropanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 426.3 (M+H)⁺.

Example 361N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclobutanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 440.3 (M+H)⁺.

Example 362N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclopentanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 454.4 (M+H)⁺.

Example 363N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclohexanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 468.3 (M+H)⁺.

Example 364N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 400.3 (M+H)⁺.

Example 365N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}propanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 414.3 (M+H)⁺.

Example 366N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}-2-methylpropanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 428.3 (M+H)⁺.

Example 367(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)quinolin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 448.3 (M+H)⁺.

Example 368(5S)-7-(3-Chloropyridin-2-yd)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 364.2 (M+H)⁺.

Example 369(5S)-7-[3-Fluoro-4-(trifluoromethyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 416.2 (M+H)⁺.

Example 370(5S)-2-(trans-4-Hydroxycylohexyl)-7-(3,5,6-trifluoro-4-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 398.2 (M+H)⁺.

Example 3712,3,5-Trifluoro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 409.2 (M+H)⁺.

Example 372(5S)-7-(3,5-Difluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 366.2 (M+H)⁺.

Example 373(5S)-2-(trans-4-hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 398.2 (M+H)⁺.

Example 374(5S)-7-(3-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 348.2 (M+H)⁺.

Example 375(5S)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 382.1 (M+H)⁺.

Example 376(5S)-7-(3-Ethynylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of(5S)-2-(trans-4-hydroxycyclohexyl)-7-{3-[(trimethylsilyl)ethynyl]pyridin-2-yl}-2,7-diazaspiro[4.5]decan-1-one(10 mg, 0.00002 mol, this compound was prepared by using proceduresanalogous to those described for the synthesis of example 93), lithiumhydroxide monohydrate (1.1 mg, 0.000026 mol) in tetrahydrofuran (0.5 mL,0.006 mol) and a couple of drops of water was stirred at rt for 30 min.The crude reaction mixture was purified by prep-HPLC to afford 7.2 mg ofthe desired product. LC-MS: 354.2 (M+H)⁺.

Example 3777-(2-Fluoro-4-nitrophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 43. LC-MS: 392.2 (M+H)⁺.

Example 3782-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methylnicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 369.2 (M+H)⁺.

Example 379(5S)-2-(trans-4-Hydroxycyclohexyl)-7-quinolin-2-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 380.3 (M+H)⁺.

Example 3802-(trans-4-Hydroxycyclohexyl)-7-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 412.3 (M+H)⁺.

Example 381(5S)-7-(3-Fluoropyridin-2-yd)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 348.2 (M+H)⁺.

Example 3827-(5-Ethylpyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 359.3 (M+H)⁺.

Example 383(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methylquinolin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 394.3 (M+H)⁺.

Example 384N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 422.2 (M+H)⁺.

Example 385(5S)-7-[2-Fluoro-4-(pyridin-4-yloxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 440.2 (M+H)⁺.

Example 386(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(hydroxymethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 360.2 (M+H)⁺.

Example 3876-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylnicotinamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 387.3 (M+H)⁺.

Example 388(5S)-7-(3-Fluoropyridin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 348.3 (M+H)⁺.

Example 389(5S)-7-(2-Chloropyridin-4-yd)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.LC-MS: 364.2 (M+H)⁺.

Example 390N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-N-methylmethanesulfonamide

A mixture ofN-{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide(20 mg, 0.00006 mol, example 312), methyl iodide (4.1 μL, 0.000066 mol),and potassium carbonate (10 mg, in excess) in acetone (2 mL, 0.03 mol)was stirred at rt for 2 h and then heated to 40° C. for 2 h. Thereaction mixture was allowed to cool to rt and was purified by prep-HPLCto afford the desired product. LC-MS: 454.2 (M+H)⁺.

Example 391N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-2-methylpropanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 415.3 (M+H)⁺.

Example 3927-(2-Chloropyrimidin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 365.2 (M+H)⁺.

Example 3936-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N,N-dimethylnicotinamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 29. LC-MS: 401.2 (M+H)⁺.

Example 394 Ethyl{2-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 447.2 (M+H)⁺.

Example 395Methyl{2-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 433.2 (M+H)⁺.

Example 396N-{2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methoxypyridin-3-yl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 417.2 (M+H)⁺.

Example 3975-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylpyridine-2-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 387.2 (M+H)⁺.

Example 398(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.Additionally, NaH was used instead of N,N-diisopropylethylamine as thebase. LC-MS: 360.2 (M+H)⁺.

Example 3992-[8-(trans-4-Hydroxycyclohexyl)-7-oxo-2,8-diazaspiro[5.5]undec-2-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 1. LC-MS: 369.2 (M+H)⁺.

Example 4002-(trans-4-Hydroxycyclohexyl)-8-[3-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[5.5]undecan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 1. LC-MS: 412.2 (M+H)⁺.

Example 4013-Cyclohexyl-7-[5-(trifluoromethyl)pyridin-2-yl]-1,3,7-triazaspiro[4.5]decane-2,4-dione

Step 1. tert-butyl 3-oxopiperidine-1-carboxylate

To a solution of pyridinium chlorochromate (3.21 g, 0.0149 mol) inmethylene chloride (18 mL) was added another solution of tert-butyl3-hydroxypiperidine-1-carboxylate (1.00 g, 0.00497 mol) in 7 mLmethylene chloride at rt. After stirring for 18 h, the reaction mixturewas diluted with diethyl ether, filtered through a bed of celite,concentrated in-vacuo, and then purified by Combiflash to afford thedesired product verified by NMR.

Step 2. tert-butyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate

A mixture of tert-butyl 3-oxopiperidine-1-carboxylate (0.20 g, 0.0010mol), potassium cyanide (0.13 g, 0.0020 mol) and ammonium carbonate(0.77 g, 0.0080 mol) in ethanol (4.0 mL, 0.068 mol) and water (2.0 mL)was stirred at 70° C. for 4 h. The mixture was then diluted with ethylacetate and washed with water, brine, dried and concentrated to give thedesired product. LC-MS: 292.0 (M+Na)⁺.

Step 3. tert-butyl3-cyclohexyl-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate

Diethyl azodicarboxylate (0.315 mL, 0.00200 mol) was added to a mixtureof tert-butyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate(269.3 mg, 0.001000 mol), cyclohexanol (0.156 mL, 0.00150 mol), andtriphenylphosphine (524 mg, 0.00200 mol) in tetrahydrofuran (6 mL, 0.08mol). The reaction mixture was stirred at room temperature overnight.The mixture was concentrated and the residue was purified by Combiflashwith ethyl acetatehexane. LC-MS: 296.2 (M−Bu+2H)⁺.

Step 4.3-cyclohexyl-7-[5-(trifluoromethyl)pyridin-2-yl]-1,3,7-triazaspiro[4.5]decane-2,4-dione

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 92, steps 3 and 4. LC-MS: 397.2(M+H)⁺.

Example 4026-(3-cyclohexyl-2,4-dioxo-1,3,7-triazaspiro[4.5]dec-7-yl)nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 401. LC-MS: 354.2 (M+H)⁺.

Example 4034-(3-Cyclohexyl-2,4-dioxo-1,3,7-triazaspiro[4.5]dec-7-yl)-3-fluorobenzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 401. LC-MS: 393.1 (M+Na)⁺, 371.1(M+H)⁺.

Example 4043-Cyclohexyl-7-(5-ethylpyrimidin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 401. LC-MS: 358.1 (M+H)⁺.

Example 4053-Cyclohexyl-7-(3-fluoropyridin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 401. LC-MS: 347.1 (M+H)⁺.

Example 4063-Cyclohexyl-7-(3,5-difluoropyridin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 401. LC-MS: 365.2 (M+H)⁺.

Example 4073-Cyclohexyl-7-(3,5-dichloropyridin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 401. LC-MS: 397.1/399.1 (M+H)⁺.

Example 4082-(3-Methylpyridin-2-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 92 starting from3-methylpyridin-2-amine and prepared as a racemic compound. LC-MS: 391.2(M+H)⁺.

Example 409N,N-Dimethyl-5-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridine-2-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 387.2 (M+H)⁺.

Example 4103-Fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 43 starting from(5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-oneprepared as described in Example 105. LC-MS: 358.2 (M+H)⁺.

Example 411(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxy-2-methylpyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 374.2 (M+H)⁺.

Example 412(5S)-2-(4-Hydroxycyclohexyl)-7-(6-methoxy-4-methylpyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 374.2 (M+H)⁺.

Example 413(5S)-7-(2,6-Difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 365.2 (M+H)⁺.

Example 4147-(5-Chloropyridin-2-yl)-2-(4-hydroxyl-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 416.2 (M+H)⁺.

Example 4157-(3-Fluoropyridin-4-yl)-2-(4-hydroxyl-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93. LC-MS: 400.1 (M+H)⁺.

Example 416N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting fromN-{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}amineand prepared as a racemic compound. LC-MS: 470.1 (M+H)⁺.

Example 417Methyl{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting fromN-{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}amineand prepared as a racemic compound. LC-MS: 472.1 (M+H)⁺.

Example 418 Propyl{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting fromN-{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}amineand prepared as a racemic compound. LC-MS: 500.1 (M+H)⁺.

Example 419N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}ethanesulfonamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105 starting fromN-{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}amineand prepared as a racemic compound. LC-MS: 506.1 (M+H)⁺.

Example 4202-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

Step 1. benzyl(5S)-2-[cis-4-(benzoyloxy)cyclohexyl]-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate

Diethyl azodicarboxylate (163.0 μL, 0.001035 mol) was added to a mixtureof benzyl(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate(200.0 mg, 0.0005175 mol, this compound was prepared by using theprocedures of example 472-a, step 1), and triphenylphosphine (271.4 mg,0.001035 mol) in tetrahydrofuran (3.0 mL, 0.037 mol) at rt. The mixturewas stirred at rt for 5 minutes, then benzoic acid (66.36 mg, 0.0005434mol) was added. After stirring for an additional 2 h, the volatiles inthe mixture were removed in-vacuo and the residue was purified by flashchromatography to afford the desired product.

Step 2. cis-4-[(5S)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexylbenzoate

Benzyl(5S)-2-[cis-4-(benzoyloxy)cyclohexyl]-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate(0.16 g, 0.00033 mol) in methanol (5 mL, 0.1 mol) was stirred withpalladium (20 mg, 0.00002 mol) under an atmosphere of hydrogen for 2 h.The mixture was filtered and the filtrate was concentrated to afford thedesired product. LC-MS: 357.2 (M+H)⁺.

Step 3.2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

A mixture of cis-4-[(5S)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexylbenzoate (19.0 mg, 0.0000533 mol), 2-chloronicotinonitrile (8.12 mg,0.0000586 mol) and N,N-diisopropylethylamine (20.0 μL, 0.000115 mol) inN-methylpyrrolidinone (0.6 mL, 0.006 mol) was irradiated by microwave at180° C. for 20 min. After cooling to rt, lithium hydroxide aqueoussolution (1.0 M, 0.150 mL) was added, followed by methanol (0.2 mL). Themixture was heated at 100° C. for 5 h. The crude reaction mixture wasthen purified by prep-HPLC under basic conditions to afford the desiredproduct. LC-MS: 355.2 (M+H)⁺.

Example 421(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 398.2 (M+H)⁺.

Example 422(5S)-7-(3-Fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 348.2 (M+H)⁺.

Example 423(5S)-7-(3,5-Dichloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 398.1/400.2 (M+H)⁺.

Example 424(5S)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 382.2 (M+H)⁺.

Example 425(5S)-7-(3-Chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 364.2 (M+H)⁺.

Example 426Methyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 416.2 (M+H)⁺.

Example 427 Ethyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 430.3 (M+H)⁺.

Example 428 Prop-2-yn-1-yl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 440.3 (M+H)⁺.

Example 429Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 417.2 (M+H)⁺.

Example 430 Ethyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 431.3 (M+H)⁺.

Example 431 Prop-2-yn-1-yl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 441.2 (M+H)⁺.

Example 432Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 433.3 (M+H)⁺.

Example 433 Ethyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 447.3 (M+H)⁺.

Example 434 Prop-2-yn-1-yl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 457.2 (M+H)⁺.

Example 435Methyl{5-fluoro-2-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-4-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 422.2 (M+H)⁺.

Example 436 Isopropyl{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methylcarbamate

A mixture of isopropyl{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate(6 mg, 0.00001 mol, this compound was prepared by using proceduresanalogous to those described for the synthesis of example 105), methyliodide (0.5 mL, 0.008 mol), and potassium carbonate (6 mg, 0.00004 mol)was stirred at rt for 24 h at 60° C. After cooling, the reaction mixturewas purified by prep.-HPLC to afford the desired product. LC-MS: 462.3(M+H)⁺.

Example 437(5S)-7-(3-Bromo-5-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of Example 472-a). LC-MS: 422.2/424.2 (M+H)⁺.

Example 4382-[(5S)-2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one (which was preparedusing procedures analogous to those described for the synthesis ofExample 92). LC-MS: 339.2 (M+H)⁺.

Example 4392-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a). LC-MS: 355.2 (M+H)⁺.

Example 440(5S)-7-(3-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a). LC-MS: 362.2 (M+H)⁺.

Example 4416-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylnicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 5472-a). LC-MS: 369.2 (M+H)⁺.

Example 4422-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4,6-dimethylnicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a). LC-MS: 383.2 (M+H)⁺.

Example 443(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazolin-4-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a). LC-MS: 449.1 (M+H)⁺.

Example 444(5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 416.1 (M+H)⁺.

Example 445(5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 414.1 (M+H)⁺.

Example 446(5S)-7-(3-Fluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 334.1 (M+H)⁺.

Example 447(5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 418.1 (M+H)⁺.

Example 448(5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazinan-3-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 432.2 (M+H)⁺.

Example 449(5S)-7-[2-Fluoro-4-(2-oxopiperidin-1-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 430.2 (M+H)⁺.

Example 450(5S)-7-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 416.2 (M+H)⁺.

Example 4513-Fluoro-N-methyl-4-[(5S)-d-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 390.2 (M+H)⁺.

Example 4523-Fluoro-N,N-dimethyl-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 404.2 (M+H)⁺.

Example 4532-[(5S)-1-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 340.2 (M+H)⁺.

Example 454(5S)-7-(3,5-Dichloropyridin-2-yl)-2-(3-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116 starting from(S)-2-(3-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one (which wasprepared using procedures analogous to those described for the synthesisof example 92). LC-MS: 391.1 (M+H)⁺.

Example 4553-Bromo-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 432.1/434.1 (M+H)⁺.

Example 456(5S)-7-(2,5-difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 365.2 (M+H)⁺.

Example 457(5S)-7-(2-Bromo-3-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 425.1/427.1 (M+H)⁺.

Example 458(5S)-7-(5-Fluoro-2-methylphenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 361.2 (M+H)⁺.

Example 459(5S)-7-(2,3-Dichlorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 397.1/399.1 (M+H)⁺.

Example 460(5S)-7-(2,6-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 397.1/399.1 (M+H)⁺.

Example 4614-Bromo-2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 432.1 (M+H)⁺.

Example 4622-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 354.2 (M+H)⁺.

Example 463(5S)-7-(2-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 44 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by Pd catalyzed hydrogenation toremove the Cbz protecting group). LC-MS: 347.2 (M+H)⁺.

Example 4642-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 355.2 (M+H)⁺.

Example 465(5S)-7-(3-Bromo-5-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 426.1/428.1 (M+H)⁺.

Example 466(5S)-7-(3-Fluoro-4-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 362.2 (M+H)⁺.

Example 4676-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylnicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 369.2 (M+H)⁺.

Example 468(5S)-7-(5-Chloro-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 378.1 (M+H)⁺.

Example 4694-Chloro-2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 388.1 (M+H)⁺.

Example 4702-Fluoro-4-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 372.1 (M+H)⁺.

Example 4714-Bromo-2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 432.1 (M+H)⁺.

Example 4727-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 1. LC-MS: 441.2/443.2 (M+H)⁺.

Example 472-a(5S)-7-[2-Chloro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

Step 1. Benzyl(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate

A mixture of 1-benzyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate(1.0 g, 0.0030 mol, prepared by using procedures analogous to thosedescribed for the synthesis of example 1, steps 1 and 2),trans-4-aminocyclohexanol hydrochloride (0.50 g, 0.0033 mol), andtriethylamine (0.48 g, 0.0048 mol) in 1,2-dichloroethane (8 mL, 0.1 mol)was stirred at rt for 30 min. To the mixture was added sodiumtriacetoxyborohydride (1.6 g, 0.0075 mol) and the resulting mixture wasstirred at rt for 1 h. The reaction mixture then was warmed to 80° C.with stirring for 16 h. After cooling to ambient temperature, thereaction mixture was diluted with dichloromethane and the solution waswashed with 1N HCl, water, brine, and dried over MgSO₄. Afterfiltration, the filtrate was concentrated in-vacuo and the resultingresidue was purified by flash column chromatography to afford 1.04 g ofthe desired product. Further purification by chiral HPLC was carried out(Chiralcel OD-H column (3.0×25 cm, 5 micron particle size, ChiralTechnologies; Item number 14475) eluting with 15% ethanol/hexanes(isocratic, 26 mL/min.); Detection: 220 nm; retention time: 10.0 minutefor peak 1, 12.5 minute for peak 2). The first peak to elute was foundto be the R configuration and the second peak was found to be the Sconfiguration and used for analog synthesis. LC-MS: 387.3 (M+H)⁺.

Step 2. Benzyl(5S)-1-oxo-2-trans-4-[(triethylsilyl)oxy]cyclohexyl)-2,7-diazaspiro[4.5]decane-7-carboxylate

To a solution of benzyl(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate(2.0 g, 0.0052 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) were added1H-imidazole (0.986 g, 0.0145 mol) and chlorotriethylsilane (1.13 mL,0.00673 mol) at rt. After stirring for 2 h ice-water was added and theresulting mixture was stirred at room temperature for 30 minutes andextracted three times with AcOEt. The combined extracts were washed withbrine, dried over sodium sulfate, and concentrated. The residual oil waspurified by column chromatography using 30% by volume AcOEt in hexanes.

Step 3.(5S)-2-trans-4-[(triethylsilyl)oxy]cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

To a solution of benzyl(5S)-1-oxo-2-{trans-4-[(triethylsilyl)oxy]cyclohexyl}-2,7-diazaspiro[4.5]decane-7-carboxylate(2.4 g, 0.0048 mol) in methanol (10 mL, 0.2 mol) was added Pd/C, and thesuspension was stirred at rt under a H₂ balloon for 1.5 h. Theinorganics were filtered and the filtrate was concentrated to afford thedesired product.

Step 4.(5S)-7-[2-chloro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

A mixture of 2-bromo-1-chloro-4-(trifluoromethyl)benzene (26 mg, 0.0001mol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.000002 mol),2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (5 mg, 0.00001mol) in 1,4-dioxane (0.5 mL, 0.006 mol) was stirred under N₂ (g) for 20min. To this mixture were added(5S)-2-{trans-4-[(triethylsilyl)oxy]cyclohexyl}-2,7-diazaspiro[4.5]decan-1-one(30 mg, 0.00008 mol) and sodium tert-butoxide (11.8 mg, 0.000123 mol),and the resulting mixture was degassed and stirred at 100° C. for 16 h.At this time 1M TBAF (tetra-n-butylammonium fluoride) in THF (0.3 mL)was added dropwise to the reaction mixture and the solution was stirredat rt for 1 h. The volatiles were removed in-vacuo and the residue waspurified by prep-HPLC to afford the desired product. LC-MS: 431.1(M+H)⁺.

Example 473(5S)-7-[3-Fluoro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 472-a. LC-MS: 415.1 (M+H)⁺.

Example 474(5S)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 472-a. LC-MS: 377.4 (M+H)⁺.

Example 475(5S)-7-(3-chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 472-a. LC-MS: 377.4 (M+H)⁺.

Example 476(5S)-2-(trans-4-Hydroxycyclohexyl)-7-quinolin-8-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 472-a. LC-MS: 380.2 (M+H)⁺.

Example 477{3-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 472-a. LC-MS: 368.2 (M+H)⁺.

Example 478(5S)-7-(4-Fluoro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 361.2 (M+H)⁺.

Example 479(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxopyrrolidin-1-yl)-2-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 480.2 (M+H)⁺.

Example 480(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-1,3-oxazolidin-3-yl)-2-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 482.2 (M+H)⁺.

Example 481(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-1,3-oxazinan-3-yl)-2-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 496.2 (M+H)⁺.

Example 482(5S)-7-[3-Fluoro-4-(pyridin-2-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 440.3 (M+H)⁺.

Example 483(5S)-7-[3-Fluoro-4-(pyridin-4-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 440.3 (M+H)⁺.

Example 484(5S)-7-[3-Fluoro-4-(pyridin-3-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 440.3 (M+H)⁺.

Example 485(5S)-7-[2-Fluoro-4-(pyridin-3-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 440.3 (M+H)⁺.

Example 486Methyl{3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 436.3 (M+H)⁺.

Example 487 Ethyl{3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 450.3 (M+H)⁺.

Example 488 Prop-2-yn-1-yl{3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 460.3 (M+H)⁺.

Example 489 Propyl{3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 465.1 (M+H)⁺.

Example 490N-{3-Chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopentanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 475.1 (M+H)⁺.

Example 491N-{3-Chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclohexanecarboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 489.1 (M+H)⁺.

Example 492(5S)-7-(5-Fluoropyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((cis)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 349.1 (M+H)⁺.

Example 493(5S)-7-(5-Bromopyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((cis)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group). LC-MS: 409.1/411.1(M+H)⁺.

Example 494(5S)-7-(5-Ethylpyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((cis)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (whichwas prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 359.1 (M+H)⁺.

Example 4954-{2-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 450.1 (M+H)⁺.

Example 496N-Cyclopropyl-4-{2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 490.1 (M+H)⁺.

Example 497(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(4-methoxyphenyl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 437.1 (M+H)⁺.

Example 498(5S)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-3-ylpyrimidine-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 408.2 (M+H)⁺.

Example 4995-{2-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}-N,N-dimethylpyridine-2-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 479.1 (M+H)⁺.

Example 500(5S)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-4-ylpyrimidin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 408.2 (M+H)⁺.

Example 5014-{5-Chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-N-cyclopropylbenzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 523.2 (M+H)⁺.

Example 5025′-Chloro-N-ethyl-6′-[(5S)-2-(cis-4-hydroxycyclohexyl)-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3,3′-bipyridine-6-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 512.2 (M+H)⁺.

Example 5032-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 355.2 (M+H)⁺.

Example 504Methyl{4-[(5S)-2-(cis-4-hydroxy-4-methylcyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 430.1 (M+H)⁺.

Example 505 Prop-2-yn-1-yl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 105. LC-MS: 457.2 (M+H)⁺.

Example 506(5S)-7-(5-Fluoropyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 335.1 (M+H)⁺.

Example 507(5S)-7-(5-Ethylpyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 345.1 (M+H)⁺.

Example 508(5S)-2-(Tetrahydro-2H-pyran-4-yl)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 385.1 (M+H)⁺.

Example 509(5S)-7-(4-Methoxypyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 116. LC-MS: 347.1 (M+H)⁺.

Example 510(5S)-7-(2-Fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 180. LC-MS: 333.1 (M+H)⁺.

Example 511(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(1H-pyrazol-1-yl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

To a solution of(5S)-7-(5-bromopyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(30 mg, 0.00007 mol, this compound was prepared by using procedures thatwere analogous to those described for the synthesis of example 420) in1,4-dioxane (1 mL, 0.01 mol) was added 1H-pyrazole (6.0 mg, 0.0000880mol), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.3 μL, 0.000015mol), copper(I) iodide (1.4 mg, 0.0000073 mol), and potassium carbonate(0.0213 g, 0.000154 mol). After stirring at 150° C. for 16 h, thereaction mixture was filtered and purified by prep-HPLC to afford thedesired product. LC-MS: 397.2 (M+H)⁺.

Example 512(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(3-methyl-1H-pyrazol-1-yl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 511. LC-MS: 411.2 (M+H)⁺.

Example 513(5S)-2-(cis-4-Hydroxycyclohexyl)-7-{5-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-2-yl}-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 511. LC-MS: 465.2 (M+H)⁺.

Example 514(5S)-2-(cis-4-Hydroxycyclohexyl)-7-pyrimidin-2-yl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 331.2 (M+H)⁺.

Example 515(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(2-oxopyridin-1(2H)-yl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 511. LC-MS: 424.2 (M+H)⁺.

Example 516(5S)-7-(2,5-Difluoropyridin-3-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 366.1 (M+H)⁺.

Example 517(5S)-7-(3,5-Difluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 366.1 (M+H)⁺.

Example 518(5S)-7-[3-Fluoro-4-(trifluoromethyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 416.1 (M+H)⁺.

Example 519(5S)-7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 432.2 (M+H)⁺.

Example 520(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 398.2 (M+H)⁺.

Example 521(5S)-7-(5-Bromo-2-chloropyridin-3-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 442.2/444.2 (M+H)⁺.

Example 522a(5S)-7-(5-Bromo-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 426.1 (M+H)⁺.

Example 522b(5S)-7-(5-Bromo-3-chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 442.2/444.2 (M+H)⁺.

Example 523(5S)-7-(5-Bromo-3-methylpyridin-2-yd)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 420. LC-MS: 422.2/424.2 (M+H)⁺.

Example 524Methyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of examples 420, steps 1 and 2 followed byusing procedures that were analogous to those described for thesynthesis of example 105, steps 1 and 2. LC-MS: 417.2 (M+H)⁺.

Example 525 Ethyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 431.2 (M+H)⁺.

Example 526 Propyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 445.2 (M+H)⁺.

Example 527 Prop-2-yn-1-yl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 441.2 (M+H)⁺.

Example 528Methyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 433.2 (M+H)⁺.

Example 529 Ethyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 447.2 (M+H)⁺.

Example 530 Propyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 461.2 (M+H)⁺.

Example 531 Prop-2-yn-1-yl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 457.2 (M+H)⁺.

Example 532(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxopyrrolidin-2-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of examples 420, steps 1 and 2 followed byusing procedures that were analogous to those described for thesynthesis of example 256. LC-MS: 443.2 (M+H)⁺.

Example 533(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 532. LC-MS: 445.2 (M+H)⁺.

Example 534(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 532. LC-MS: 459.1 (M+H)⁺.

Example 535(5S)-7-(3-Chloro-5-phenylpyridin-2-yd)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of examples 420, steps 1 and 2 followed byusing procedures that were analogous to those described for thesynthesis of example 257. LC-MS: 440.2 (M+H)⁺.

Example 536a(5S)-7-[3-Chloro-5-(4-methoxyphenyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 535. LC-MS: 471.2 (M+H)⁺.

Example 536b4-{5-Chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 535. LC-MS: 483.2 (M+H)⁺.

Example 537(5S)-7-(5-Chloro-3,4′-bipyridin-6-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 535. LC-MS: 441.2 (M+H)⁺.

Example 5385′-Chloro-6′-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N,N-dimethyl-3,3′-bipyridine-6-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 535. LC-MS: 512.2 (M+H)⁺.

Example 5395′-Chloro-N,N-diethyl-6′-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3,3′-bipyridine-6-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 535. LC-MS: 540.2 (M+H)⁺.

Example 5404-{5-Chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-N,N-dimethylbenzamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 535. LC-MS: 511.2 (M+H)⁺.

Example 541 Methyl{5-chloro-6-[(5S)-2-(cis-4-hydroxycylohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 437.2 (M+H)⁺.

Example 542 Ethyl{5-chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 451.2 (M+H)⁺.

Example 543 Propyl{5-chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 465.2 (M+H)⁺.

Example 544 Prop-2-yn-1-yl{5-chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate

This compound was prepares by using procedures analogous to thosedescribed for the synthesis of example 524. LC-MS: 461.2 (M+H)⁺.

Example 545(5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 532. LC-MS: 449.2 (M+H)⁺.

Example 546(5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 532. LC-MS: 463.2 (M+H)⁺.

Example 547(5S)-7-[3-Chloro-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 532. LC-MS: 447.2 (M+H)⁺.

Example 548(5S)-7-(5-Chloro-3,3′-bipyridin-6-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 535. LC-MS: 441.2 (M+H)⁺.

Example 549(5S)-7-(3-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 362.2 (M+H)⁺.

Example 5506-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylnicotinonitrile

This compound was prepares by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group). LC-MS: 369.2 (M+H)⁺.

Example 5512-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4,6-dimethylnicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 383.2 (M+H)⁺.

Example 552(5S)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazolin-4-yl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 449.2 (M+H)⁺.

Example 553(5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 414.2 (M+H)⁺.

Example 554(5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 416.2 (M+H)⁺.

Example 555(5S)-7-(5-Chloro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 378.2 (M+H)⁺.

Example 556(5S)-7-(3-Fluoro-4-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a and followed by standard hydrogenation toremove the carbobenzyloxy (Cbz) protecting group). LC-MS: 362.2 (M+H)⁺.

Example 557(5S)-7-(5-Fluoro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 362.2 (M+H)⁺.

Example 558(5S)-7-(5-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 362.2 (M+H)⁺.

Example 559(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 370.2 (M+H)⁺.

Example 560(5S)-2-(trans-4-Hydroxycyclohexyl)-7-(5-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 93 starting from(S)-2-((trans)-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(which was prepared using procedures analogous to those described in thesynthesis of example 472-a followed by standard hydrogenation to removethe carbobenzyloxy (Cbz) protecting group). LC-MS: 344.2 (M+H)⁺.

Example 5612-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-phenylnicotinonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 257. LC-MS: 431.2 (M+H)⁺.

Example 562(5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 433.2 (M+H)⁺.

Example 563(5S)-7-[3-Chloro-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 431.2 (M+H)⁺.

Example 564(5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 447.2 (M+H)⁺.

Example 565(5S)-7-[3-Chloro-5-(2-oxopiperidin-1-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of example 256. LC-MS: 445.2 (M+H)⁺.

Example A Enzymatic assay of 11βHSD1

All in vitro assays were performed with clarified lysates as the sourceof 11βHSD1 activity. HEK-293 transient transfectants expressing anepitope-tagged version of full-length human 11βHSD1 were harvested bycentrifugation. Roughly 2×10⁷ cells were resuspended in 40 mL of lysisbuffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl₂ and 250 mMsucrose) and lysed in a microfluidizer. Lysates were clarified bycentrifugation and the supernatants were aliquoted and frozen.

Inhibition of 11βHSD1 by test compounds was assessed in vitro by aScintillation Proximity Assay (SPA). Dry test compounds were dissolvedat 5 mM in DMSO. These were diluted in DMSO to suitable concentrationsfor the SPA assay. 0.8 μL of 2-fold serial dilutions of compounds weredotted on 384 well plates in DMSO such that 3 logs of compoundconcentration were covered. 20 μL of clarified lysate was added to eachwell. Reactions were initiated by addition of 20 μL ofsubstrate-cofactor mix in assay buffer (25 mM Tris-HCl, pH 7.5, 0.1 MNaCl, 1 mM MgCl₂) to final concentrations of 400 μM NADPH, 25 nM3H-cortisone and 0.007% Triton X-100. Plates were incubated at 37° C.for one hour. Reactions were quenched by addition of 40 μL of anti-mousecoated SPA beads that had been pre-incubated with 10 μM carbenoxoloneand a cortisol-specific monoclonal antibody. Quenched plates wereincubated for a minimum of 30 minutes at RT prior to reading on aTopcount scintillation counter. Controls with no lysate, inhibitedlysate, and with no mAb were run routinely. Roughly 30% of inputcortisone is reduced by 11βHSD1 in the uninhibited reaction under theseconditions.

Test compounds having an IC₅₀ value less than about 20 μM according tothis assay were considered active.

Example B Cell-Based Assays for HSD Activity

Peripheral blood mononuclear cells (PBMCs) were isolated from normalhuman volunteers by Ficoll density centrifugation. Cells were plated at4×10⁵ cells/well in 200 μL of AIM V (Gibco-BRL) media in 96 well plates.The cells were stimulated overnight with 50 ng/ml recombinant human IL-4(R&D Systems). The following morning, 200 nM cortisone (Sigma) was addedin the presence or absence of various concentrations of compound. Thecells were incubated for 48 hours and then supernatants were harvested.Conversion of cortisone to cortisol was determined by a commerciallyavailable ELISA (Assay Design).

Test compounds having an IC₅₀ value less than about 20 μM according tothis assay were considered active.

Example C Cellular Assay to Evaluate MR Antagonism

Assays for MR antagonism were performed essentially as described(Jausons-Loffreda et al. J Biolumin and Chemilumin, 1994, 9: 217-221).Briefly, HEK293/MSR cells (Invitrogen Corp.) were co-transfected withthree plasmids: 1) one designed to express a fusion protein of the GAL4DNA binding domain and the mineralocorticoid receptor ligand bindingdomain, 2) one containing the GAL4 upstream activation sequencepositioned upstream of a firefly luciferase reporter gene (pFR-LUC,Stratagene, Inc.), and 3) one containing the Renilla luciferase reportergene cloned downstream of a thymidine kinase promoter (Promega).Transfections were performed using the FuGENE6 reagent (Roche).Transfected cells were ready for use in subsequent assays 24 hourspost-transfection.

In order to evaluate a compound's ability to antagonize the MR, testcompounds are diluted in cell culture medium (E-MEM, 10%charcoal-stripped FBS, 2 mM L-glutamine) supplemented with 1 nMaldosterone and applied to the transfected cells for 16-18 hours. Afterthe incubation of the cells with the test compound and aldosterone, theactivity of firefly luciferase (indicative of MR agonism by aldosterone)and Renilla luciferase (normalization control) were determined using theDual-Glo Luciferae Assay System (Promega). Antagonism of themineralocorticoid receptor was determined by monitoring the ability of atest compound to attenuate the aldosterone-induced firefly luciferaseactivity.

Compounds having an IC₅₀ of 100 μM or less were considered active.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula I:

or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z; L is (CR¹²R¹³)_(q1), (CR¹²R¹³)_(q1)O(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)S(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), or (CR¹²R¹³)_(q1)CO(CR¹²R¹³)_(q2); Q is —(CR¹R²)_(m)-A; A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′; E is —(CR^(3a)R^(3b))_(n1)—, —(CR^(3a)R^(3b))_(n2)CO—, —(CR^(3a)R^(3b))_(n2)OCO—, —(CR^(3a)R^(3b))_(n2)SO—, —(CR^(3a)R^(3b))_(n2)SO₂—, —(CR^(3a)R^(3b))_(n2)NR^(3c)—, —(CR^(3a)R^(3b))_(n3)CONR^(3c)—, —(CR^(3a)R^(3b))_(n2)NR^(3c)CO—, or a group of formula:

D¹, D², D³ and D⁴ are each N or CR¹⁵; R¹ and R² are each, independently, H or C₁₋₈ alkyl; R^(3a) and R^(3b) are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(C′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R¹⁶; R^(3c) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or CO—(C₁₋₄ alkyl); R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(c′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R¹⁴; or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁶ and R⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁸ and R⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R¹⁰ and R¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁴ and R⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁶ and R⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁴ and R⁹ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁴ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁶ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁹ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; R¹² and R¹³ are each, independently, H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′)R^(d′); R¹⁴ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′)R^(d′); R¹⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″R) ^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), or S(O)₂NR^(c″)R^(d″); R¹⁶ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′R) ^(d′); W, W′ and W″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; X, X′ and X″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; Y, Y′ and Y″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; Z, Z′ and Z″ are each, independently, H, halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(d), NR^(e)S(O)₂R^(b), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d); wherein two —W—X—Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″; wherein two —W′—X′—Y′-Z′ attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″; wherein —W—X—Y-Z is other than H; wherein —W′—X′—Y′-Z′ is other than H; wherein —W″—X″—Y″-Z″ is other than H; R^(a), R^(a′) and R^(a″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(b), R^(b′) and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(c) and R^(d) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c) and R^(d) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c′) and R^(d′) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c′) and R^(d′) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c″) and R^(d″) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c″) and R^(d″) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(e) and R^(f) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(e) and R^(f) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; m is 0, 1, 2 or 3; n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; p is 0, 1 or 2; q1 is 0, 1 or 2; q2 is 0, 1 or 2; and r is 0, 1 or
 2. with the provisos: (a) when A is aryl optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′ or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′; L is SO₂, SO₂CH₂ or CH₂; and m is 0, then Cy is other than unsubstituted aryl, mono substituted aryl, unsubstituted heteroaryl, or monosubstituted heteroaryl; (b) when A is aryl optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′ or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′; L is SO₂, SO₂CH₂ or CH₂; m is O, and Cy is di-, tri-, tetra- or penta-substituted aryl or di-, tri-, tetra- or penta-substituted heteroaryl, then said di-, tri-, tetra- or penta-substituted aryl or di-, tri-, tetra- or penta-substituted heteroaryl is substituted by at least one C₁₋₆ alkyl and at least one halo; (c) when A is aryl optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′ or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′; L is SO₂, SO₂CH₂ or CH₂; and m is 0, then Cy is other than 2-chloro-6-methyl-phenyl; (d) when A is phenyl or 4-phenoxyphenyl; L is SO₂ or SO₂CH₂; and m is 0 or 1, then Cy is other than cyclohexyl or 1,1-dioxo-tetrahydro-thien-3-yl; (e) when Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z; L is SO₂, SO₂CH₂ or CH₂; and m is 0, then A is other than tetrahydropyran-4-yl, 2,3-dihydroinden-2-yl or 2,2-difluoro-1,3-benzodioxol-5-yl; and (f) when Cy is aryl optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z or heteroaryl optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z; L is SO₂, SO₂CH₂ or CH₂; and m is 1, then A is other than pyridine-4-yl, phenyl, 2-chloro-6-fluoro-phenyl, 4-methoxyphenyl or 4-phenoxy-phenyl.
 2. The compound of claim 1 wherein Cy is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.
 3. The compound of claim 1 wherein Cy is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z wherein W is O or absent, X is absent, and Y is absent.
 4. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.
 5. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.
 6. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 halo, CN, NO₂, C₁₋₄ alkoxy, heteroaryloxy, C₂₋₆ alkynyl, C₁₋₄ haloalkoxy, NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(e)S(O)₂R^(b), C₁₋₄ haloalkyl, C₁₋₆ alkyl, heterocycloalkyl, aryl or heteraryl, wherein each of said C₁₋₆ alkyl, aryl or heteraryl is optionally substituted by 1, 2 or 3 halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)NR^(c)R^(d), NR^(c)C(O)R^(d) or COOR^(a).
 7. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl thienyl, thiazolyl, pyrazinyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-d]pyrimidinyl, or 1,3-benzothiazolyl, each optionally substituted with 1, 2, 3 or 4 substituents independently selected form: halo, CN, NO₂, C₁₋₄ alkoxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, C₂₋₆ alkynyl, C₁₋₄ haloalkoxy, NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(e)S(O)₂R^(b), C₁₋₄haloalkyl, C₁₋₆ alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl, 2-oxo-[1,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2-oxopiperidinyl, and 2-oxo-[1,3]oxazinanyl; wherein each of said C₁₋₆ alkyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, 1,2,3,6-tetrahydro-pyridinyl, 2-oxo-(2H)-pyridinyl, 2-oxo-[1,3]oxazolidinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, 2-oxopiperidinyl, or 2-oxo-[1,3]oxazinanyl is optionally substituted by 1, 2 or 3 halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)NR^(c)R^(d), NR^(c)C(O)R^(d) or COOR^(a).
 8. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl or aryl, wherein said C₁₋₆ alkyl or aryl is optionally substituted by 1, 2 or 3 halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a), or SR^(a).
 9. The compound of claim 1 wherein Cy is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl or thienyl, each optionally substituted with 1, 2, or 3 halo, CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl or aryl, wherein said C₁₋₆ alkyl or aryl is optionally substituted by 1, 2 or 3 halo or C₁₋₆ alkyl.
 10. The compound of claim 1 wherein Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.
 11. The compound of claim 1 wherein Cy is phenyl, pyridyl, pyrimidinyl, quinolinyl, or isoquinolinyl, each optionally substituted with 1, 2, or 3 halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, —NR^(e)C(O)O-Z, —C(O)O-Z, or NR^(e)C(O)-Z.
 12. The compound of claim 1 wherein Cy is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.
 13. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, 2-oxo-[1,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.
 14. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z.
 15. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, 2-oxo-[1,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, or 3 aryl or heteroaryl, wherein each of said aryl or heteroaryl is optionally substituted by 1, 2 or 3 halo, CN, C₁₋₄ alkyl, phenyl, pyridyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkyl.
 16. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, 2-oxo-[1,3]oxazinanyl, or piperizinyl, each optionally substituted with 1, 2, or 3 phenyl, pyridyl or quinolinyl, wherein each of said phenyl, pyridyl, quinolinyl is optionally substituted by 1, 2 or 3 halo, CN, C₁₋₄ alkyl, phenyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkyl.
 17. The compound of claim 1 wherein Cy is piperidinyl, pyrrolindinyl, 1,2,3,6-tetrahydropyridinyl, or piperizinyl, each optionally substituted with 1, 2, or 3 aryl, wherein said aryl is optionally substituted by 1, 2 or 3 halo or C₁₋₄ haloalkyl.
 18. The compound of claim 1 wherein L is (CR¹²R¹³)_(q1)S(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), or (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2).
 19. The compound of claim 1 wherein L is (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2).
 20. The compound of claim 1 wherein L is S, SO or SO₂.
 21. The compound of claim 1 wherein L is SO₂.
 22. The compound of claim 1 wherein L is CO.
 23. The compound of claim 1 wherein L is (CR¹²R¹³)_(q1).
 24. The compound of claim 1 wherein L is (CR¹²R¹³)_(q1) and q1 is
 0. 25. The compound of claim 1 wherein Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′.
 26. The compound of claim 1 wherein Q is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 halo, C₁₋₄ alkyl, CN, NR^(c)C(O)R^(d) or NR^(e)S(O)₂R^(b).
 27. The compound of claim 1 wherein Q is phenyl, pyridyl or quinolinyl, each optionally substituted with 1 or 2 halo, C₁₋₄ alkyl, CN, NR^(c)C(O)R^(d) or NR^(e)S(O)₂R^(b).
 28. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′.
 29. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1 or 2 —W′X′—Y′-Z′.
 30. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, C₁₋₄ alkoxy, CN, C₁₋₄ alkyl, —O-heteroaryl, —(C₁₋₄ alkyl)-CN, COOR^(a), C(O)NR^(c)R^(d) or NR^(c)C(O)OR^(a).
 31. The compound of claim 1 wherein Q is cyclopropyl, cyclohexyl, cycloheptyl, adamantyl, tetrahydro-2H-pyranyl or piperidinyl, each optionally substituted with 10H, C₁₋₄ alkoxy, CN, C₁₋₄ alkyl, —O-heteroaryl, —(C₁₋₄ alkyl)-CN, COOR^(a), C(O)NR^(c)R^(d) or NR^(c)C(O)OR^(a).
 32. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, halo, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, NR^(e)COO(C₁₋₄ alkyl), NR^(e)CO(C₁₋₄ alkyl), aryl, heteroaryl, —O-aryl, —O-heteroaryl, or —(C₁₋₄ alkyl)-OH.
 33. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, —O-heteroaryl, or C(O)O-Z′.
 34. The compound of claim 1 wherein Q is cycloalkyl or heterocycloalkyl, each substituted with at least two —W′—X′—Y′-Z′, wherein two of said at least two —W′—X′—Y′-Z′ are attached to the same atom and together with the atom to which they are attached form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″.
 35. The compound of claim 1 wherein Q is phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, indanyl, or 1,2,3,4-tetrahydronaphthalene, each optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′.
 36. The compound of claim 1 wherein Q is phenyl, pyridyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, each optionally substituted with 1, 2, 3, 4 or 5 OH, CN, halo, C₁₋₆ alkyl, —O-heteroaryl, or C(O)O-Z.
 37. The compound of claim 1 wherein Q is cyclohexyl substituted at the 4-position with at least one —W′—X′—Y′-Z′.
 38. The compound of claim 1 wherein Q is cyclohexyl substituted at the 4-position with at least one OH, CN, or —O—X′—Y′-Z′.
 39. The compound of claim 1 wherein Q is —(CR¹R²)_(m)-A and m is 1, 2 or
 3. 40. The compound of claim 1 wherein Q is —(CR¹R²)_(m)-A and m is
 2. 41. The compound of claim 30 wherein A is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′.
 42. The compound of claim 30 wherein A is aryl optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′.
 43. The compound of claim 1 wherein E is methylene, ethylene, or propylene.
 44. The compound of claim 1 wherein E is ethylene.
 45. The compound of claim 1 wherein E is CONR^(3c)—.
 46. The compound of claim 1 wherein E is a group of formula:


47. The compound of claim 1 wherein D¹, D², D³ and D⁴ are each CR¹⁵.
 48. The compound of claim 1 wherein one or two or D¹, D², D³ and D⁴ is N.
 49. The compound of claim 1 wherein R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(c′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′)S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl.
 50. The compound of claim 1 wherein R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each, independently, H, C₁₋₁₀ alkyl or C₁₋₁₀ haloalkyl.
 51. The compound of claim 1 wherein R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each H.
 52. The compound of claim 1 wherein R^(3a) and R^(3b) are each H.
 53. The compound of claim 1 wherein r is
 1. 54. The compound of claim 1 wherein r is
 0. 55. The compound of claim 1 wherein the sum of q1 and q2 is 0, 1 or
 2. 56. The compound of claim 1 wherein the sum of q1 and q2 is
 0. 57. The compound of claim 1 wherein R¹² and R¹³ are each H.
 58. The compound of claim 1 wherein at least one of R¹ and R² is C₁₋₄ alkyl.
 59. The compound of claim 1 wherein m is
 0. 60. The compound of claim 1 wherein m is 1 or
 2. 61. The compound of claim 1 wherein n1 is
 2. 62. The compound of claim 1 having Formula II:


63. The compound of claim 1 having Formula IV:


64. A compound of claim 1 selected from: 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-phenyl-2,7-diazaspiro[4.5]decan-1-one; trans-4-{7-[(3-chloro-2-methylphenyl)sulfonyl]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(4-methylpyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-2-yloxy)cyclohexyl]-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-3-yloxy)cyclohexyl]-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-[cis-4-(pyridin-4-yloxy)cyclohexyl]-2,7-diazaspiro[4.5]decan-1-one; 2-(1-Adamantyl)-7-[(3-chloro-2-methylphenyl)sulfonyl]-2,7-diazaspiro[4.5]decan-1-one; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(1-methyl-2-phenylethyl)-2,7-diazaspiro[4.5]decan-1-one; (5R)-7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-cycloheptyl-2,7-diazaspiro[4.5]decan-1-one; cis-4-{7-[(3-Chloro-2-methylphenyl)sulfonyl]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile; 2-Cyclohexyl-7-(2-fluorophenyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-(4-fluorophenyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-(3-fluorophenyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-1-one; 7-(4-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(3-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-phenyl-2,7-diazaspiro[4.5]decan-1-one; Methyl 1-[7-(2-fluorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclopropanecarboxylate; 2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 6-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; 2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-(6-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-(5-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 7-(5-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5R)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 7-(6-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-(3-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-(4-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-pyridin-2-yl-2,7-diazaspiro[4.5]decan-1-one; (5R)-2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-Cyclohexyl-7-phenyl-2,7-diazaspiro[4.5]decan-1-one; 7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 4-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 2-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; 3-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 4-(2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)benzonitrile; 4-(2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)-3-fluorobenzonitrile; 2-(trans-4-Hydroxycyclohexyl)-7-(piperidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-(pyrrolidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[(4-phenylpiperidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[(4-phenylpiperazin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one; 7-{[4-(2-Fluorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-isonicotinoyl-2,7-diazaspiro[4.5]decan-1-one; 7-Benzoyl-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-(pyridin-3-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one; 7-Benzoyl-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; Isopropyl {4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Prop-2-yn-1-yl {4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Methyl{4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; N-{4-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide; N-{4-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide; Isopropyl {3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Prop-2-yn-1-yl {3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Methyl{3-fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; N-{3-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide; 7-(4-Chloropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-pyridin-2-yl-2,7-diazaspiro[4.5]decan-1-one; 7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-(piperidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-(pyrrolidin-1-ylcarbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-[(4-phenylpiperidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-[(4-phenylpiperazin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one; 2-Cyclohexyl-7-({4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; 7-(5-Chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(3,5-Dichloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; Methyl 6-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinate; 2-(trans-4-Hydroxycyclohexyl)-7-isoquinolin-1-yl-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-quinolin-2-yl-2,7-diazaspiro[4.5]decan-1-one; N-{3-Fluoro-4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide; (5S)-2-(2-Chlorophenyl)-7-(3,5-dichloropyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-(2-Chlorophenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 2-(2-Chlorophenyl)-7-(3-chloropyrazin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-(2-Chlorophenyl)-7-(3-chloropyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-[(5S)-2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; (5S)-2-(2-Chlorophenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 6-[(5S)-2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; Methyl{6-[(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Ethyl {6-[(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Propyl {6-[(5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; 6-[2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylnicotinamide; 6-[2-(2-Chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-ethylnicotinamide; (5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5R)-2-(Tetrahydro-2H-pyran-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; Methyl{6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Ethyl {6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Propyl {6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Isopropyl {6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Isobutyl {6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; (5S)-7-(3-Chloropyrazin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; 3-[(5S)-1-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2-carbonitrile; (5)-7-(3-Chloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-[(5S)-1-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; (5S)-2-(Tetrahydro-2H-pyran-4-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3,5-Dichloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(5-Chloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.]decan-1-one; Methyl{5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Ethyl {5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Propyl {5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Isopropyl {5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Isobutyl {5-chloro-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; 3-Chloro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 6-[(5S)-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; (5S)-7-(3,5-Difluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-Isoquinolin-1-yl-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-quinolin-2-yl-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; Methyl{5-methyl-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Ethyl {5-methyl-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Propyl {5-methyl-6-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Methyl{3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Ethyl {3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Propyl {3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Isopropyl {3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Isobutyl {3-fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Methyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Ethyl {4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Propyl {4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Isopropyl {4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Isobutyl {4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Methyl methyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; 3-Fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 2-(1-Methylpiperidin-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; Methyl 4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}piperidine-1-carboxylate; N,N-Dimethyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}piperidine-1-carboxamide; 7-(3-Chloropyrazin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-1-one; 7-(3-Chloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-1-one; 7-(3,5-Dichloropyridin-2-yl)-2-quinolin-5-yl-2,7-diazaspiro[4.5]decan-1-one; 2-(2-Methylphenyl)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 7-(4-Chloropyrimidin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(6-Chloro-7H-purin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one; 3-[2-(2-Methylphenyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrazine-2-carbonitrile; 7-(6-Chloropyrazin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(3-Chloropyrazin-2-yl)-2-(2-methylphenyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(2-Methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 2-Quinolin-5-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 2-Isoquinolin-5-yl-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 2-(4-Bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 3-Methyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}benzonitrile; N-(3-Methyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}phenyl)acetamide; N-(3-Methyl-4-{1-oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}phenyl)methanesulfonamide; 2-(3-Methylpyridin-4-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 2-(4-Methylpyridin-3-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 7-(3-Chloropyrazin-2-yl)-2-(1-methylpiperidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one; Methyl [4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; Ethyl [4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; Prop-2-yn-1-yl [4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; N-[4-[(5S)-2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]acetamide; N-[4-[(5S)-2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]methanesulfonamide; Methyl methyl[4-[(5S)-2-cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; Prop-2-yn-1-yl {5-chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Methyl{5-chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Ethyl {5-chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; N-{5-Chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}acetamide; N-{5-Chloro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}methanesulfonamide; 4-{1-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile; 4-{1-Oxo-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile; 4-{7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexanecarbonitrile; 4-[7-(3,5-Dichloropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexanecarbonitrile; 4-[7-(6-Fluoropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexanecarbonitrile; (5S)-7-(2-Fluoro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(4-methoxyphenyl)-2,7-diazaspiro[4.5]decan-1-one; 4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetonitrile; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethoxy)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethoxy)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2-Chloro-4-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-Fluoro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; (5S)-7-(2,5-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,3-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,6-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 3-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; (5S)-7-(2-Fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2-Chlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Chloro-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,4-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Chloro-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (trans-4-{1-Oxo-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexyl)acetonitrile; (trans-4-{1-Oxo-7-[4-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]dec-2-yl}cyclohexyl)acetonitrile; (trans-4-{7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-1-oxo-2,7-diazaspiro[4.5]dec-2-yl}cyclohexyl)acetonitrile; {trans-4-[7-(3,5-Dichloropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexyl}acetonitrile; {trans-4-[7-(6-Fluoropyridin-2-yl)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexyl}acetonitrile; (5SS)-2-(trans-4-Hydroxycyclohexyl)-7-(3,5,6-trifluoropyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4,6-Dimethoxypyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[4-Fluoro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,5-Difluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-(Difluoromethoxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-quinazolin-4-yl-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxypyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[6-(methylamino)-9H-purin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 7-{[4-(2-Chlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-({4-[2-(trifluoromethyl)quinolin-4-yl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-{[4-(2-methylphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one; 7-{[4-(3,4-Dichlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one; 7-[(4-Biphenyl-4-ylpiperazin-1-yl)carbonyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one; 7-{[4-(4-Chlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-{[4-(2-Ethoxyphenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-{[4-(3-methoxyphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one; 7-{[4-(3-Chlorophenyl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-2,7-diazaspiro[4.5]decan-1-one; 4-(4-{[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]carbonyl}piperazin-1-yl)benzonitrile; 7-{[4-(3,5-Dichloropyridin-4-yl)piperazin-1-yl]carbonyl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(1,3-thiazol-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-({4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(3,5-Dichloropyridin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one; Propyl {3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; 2-(4-Hydroxy-1-adamantyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; Ethyl {3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; 7-(3,5-Difluoropyridin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one; 3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 2-[2-(4-Hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; 4-[2-(4-Hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide; 2-(4-Hydroxy-1-adamantyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 7-(5-Ethylpyrimidin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(3-Fluoropyridin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one; N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide; N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide; N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide; (5S)-7-(2,3-Difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2-Chloro-3-fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3,4′-Bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-2-(trans-4-Hydroxycyclohexyl)-7-(6′-methoxy-3,3′-bipyridin-6-yl)-2,7-diazaspiro[4.5]decan-1-one; 4-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-N,N-dimethylbenzamide; 4-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide; N-Cyclopropyl-4-{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide; N-(4-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}phenyl)acetamide; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(4-methoxyphenyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[5-(4-Fluorophenyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3,3′-Bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(6′-Fluoro-3,3′-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrimidin-5-ylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 3-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide; N-(3-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}phenyl)acetamide; (5S)-7-[5-(3,5-Dimethylisoxazol-4-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 4-{2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}-N,N-dimethylbenzamide; (5S)-2-(trans-4-Methoxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; N-Cyclopropyl-4-{2-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide; (5S)-7-(5-Chloro-3,3′-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Bromopyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 4-{2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide; (5S)-7-(3,5-Difluoropyridin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(5-Chloro-3,4′-bipyridin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Ethylpyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; tert-Butyl 5-chloro-6-[(5)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate; (5S)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxopyrrolidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2-Fluoro-4-pyrrolidin-1-ylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Chloro-5-pyrrolidin-1-ylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(5-pyrrolidin-1-ylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-(trans-4-hydroxy-cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazinan-3-yl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-hydroxycyclohexyl)-7-[4-(2-oxopiperidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(1,3-Benzothiazol-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-[(5S)-2-(trans-4-Methoxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; (5S)-2-(trans-4-Methoxycyclohexyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Fluoropyrimidin-2-yl)-2-(trans-4-methoxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-{3-Chloro-5-[4-(trifluoromethoxy)phenyl]pyridin-2-yl}-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(2-Chloro-9H-purin-6-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Amino-5-fluoropyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclobutanecarboxamide; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopentanecarboxamide; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclohexanecarboxamide; Ethyl {3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Propyl {3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Isobutyl {3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-2-methylpropanamide; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}ethanesulfonamide; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; Ethyl [4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; Methyl [4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; Propyl [4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; Isobutyl [4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; Isopropyl [4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]carbamate; N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]cyclopropanecarboxamide; N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide; N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]cyclopentanecarboxamide; N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]methanesulfonamide; N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]acetamide; N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]propanamide; N-[4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-(trifluoromethyl)phenyl]-2-methylpropanamide; (5S)-7-[2-Fluoro-4-(pyridin-2-yloxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Ethyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Propyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Isobutyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Isopropyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclopropanecarboxamide; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclobutanecarboxamide; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclopentanecarboxamide; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}acetamide; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}propanamide; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-2-methylpropanamide; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}cyclohexanecarboxamide; Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate; Ethyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate; Propyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate; Methyl{3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Ethyl {3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Propyl {3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Isobutyl {3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Isopropyl {3-cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopropanecarboxamide; N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclobutanecarboxamide; N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopentanecarboxamide; N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetamide; N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide; N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-2-methylpropanamide; N-{3-Cyano-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclohexanecarboxamide; Methyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate; Ethyl {4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate; Propyl {4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate; Isobutyl {4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate; Isopropyl {4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclopropanecarboxamide; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclobutanecarboxamide; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclopentanecarboxamide; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}cyclohexanecarboxamide; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}acetamide; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}propanamide; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}-2-methylpropanamide; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)quinolin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(3-Chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Fluoro-4-(trifluoromethyl)pyridin-2-yl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(3,5,6-trifluoro-4-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2,3,5-Trifluoro-6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile; (5S)-7-(3,5-Difluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(3-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Ethynylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(2-Fluoro-4-nitrophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methylnicotinonitrile; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-quinolin-2-yl-2,7-diazaspiro[4.5]decan-1-one; 2-(trans-4-Hydroxycyclohexyl)-7-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Fluoropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(5-Ethylpyrimidin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methylquinolin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; N-{4-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide; (5S)-7-[2-Fluoro-4-(pyridin-4-yloxy)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[5-(hydroxymethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; 6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylnicotinamide; (5)-7-(3-Fluoropyridin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(2-Chloropyridin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; N-{3-Fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}-N-methylmethanesulfonamide; N-{6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-2-methylpropanamide; 7-(2-Chloropyrimidin-4-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 6-[2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N,N-dimethylnicotinamide; Ethyl {2-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methoxypyridin-3-yl}carbamate; Methyl{2-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methoxypyridin-3-yl}carbamate; N-{2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-6-methoxypyridin-3-yl}acetamide; 5-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N-methylpyridine-2-carboxamide; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(3-methoxypyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 2-[8-(trans-4-Hydroxycyclohexyl)-7-oxo-2,8-diazaspiro[5.5]undec-2-yl]nicotinonitrile; 2-(trans-4-Hydroxycyclohexyl)-8-[3-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[5.5]undecan-1-one; 3-Cyclohexyl-7-[5-(trifluoromethyl)pyridin-2-yl]-1,3,7-triazaspiro[4.5]decane-2,4-dione; 6-(3-cyclohexyl-2,4-dioxo-1,3,7-triazaspiro[4.5]dec-7-yl)nicotinonitrile; 4-(3-Cyclohexyl-2,4-dioxo-1,3,7-triazaspiro[4.5]dec-7-yl)-3-fluorobenzonitrile; 3-Cyclohexyl-7-(5-ethylpyrimidin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 3-Cyclohexyl-7-(3-fluoropyridin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 3-Cyclohexyl-7-(3,5-difluoropyridin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 3-Cyclohexyl-7-(3,5-dichloropyridin-2-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 2-(3-Methylpyridin-2-yl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; N,N-Dimethyl-5-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]pyridine-2-carboxamide; 3-Fluoro-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(6-methoxy-2-methylpyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(4-Hydroxycyclohexyl)-7-(6-methoxy-4-methylpyridin-3-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,6-Difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(5-Chloropyridin-2-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one; 7-(3-Fluoropyridin-4-yl)-2-(4-hydroxy-1-adamantyl)-2,7-diazaspiro[4.5]decan-1-one; N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}propanamide; Methyl{3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Propyl {3-fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; N-{3-Fluoro-4-[2-(4-hydroxy-1-adamantyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}ethanesulfonamide; 2-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(3-Fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3,5-Dichloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Chloro-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(3-Chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; Methyl{4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylphenyl}carbamate; Ethyl {4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylphenyl}carbamate; Prop-2-yn-1-yl {4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylphenyl}carbamate; Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4-methylpyridin-3-yl}carbamate; Ethyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4-methylpyridin-3-yl}carbamate; Prop-2-yn-1-yl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4-methylpyridin-3-yl}carbamate; Methyl{6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; Ethyl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; Prop-2-yn-1-yl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; Methyl{5-fluoro-2-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-4-yl}carbamate; Isopropyl {3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methylcarbamate; (5S)-7-(3-Bromo-5-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-[(5S)-2-Cyclohexyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]nicotinonitrile; 2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile; (5S)-7-(3-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylnicotinonitrile; 2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4,6-dimethylnicotinonitrile; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazolin-4-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Fluoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxo-1,3-oxazinan-3-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxopiperidin-1-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; 3-Fluoro-N-methyl-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzamide; 3-Fluoro-N,N-dimethyl-4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzamide; 2-[(5S)-1-Oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; (5S)-7-(3,5-Dichloropyridin-2-yl)-2-(3-methylpyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 3-Bromo-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; (5S)-7-(2,5-difluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(2-Bromo-3-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(5-Fluoro-2-methylphenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,3-Dichlorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,6-Dichlorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 4-Bromo-2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; (5S)-7-(2-Fluorophenyl)-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 2-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile; (5S)-7-(3-Bromo-5-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Fluoro-4-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 6-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylnicotinonitrile; (5S)-7-(5-Chloro-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 4-Chloro-2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 2-Fluoro-4-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 4-Bromo-2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]benzonitrile; 7-[(3-Chloro-2-methylphenyl)sulfonyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Chloro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Fluoro-5-(trifluoromethyl)phenyl]-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-chloro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-quinolin-8-yl-2,7-diazaspiro[4.5]decan-1-one; {3-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}acetonitrile; (5S)-7-(4-Fluoro-2-methylphenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxopyrrolidin-1-yl)-2-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-1,3-oxazolidin-3-yl)-2-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[4-(2-oxo-1,3-oxazinan-3-yl)-2-(trifluoromethyl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Fluoro-4-(pyridin-2-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Fluoro-4-(pyridin-4-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Fluoro-4-(pyridin-3-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[2-Fluoro-4-(pyridin-3-yloxy)phenyl]-2-(4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; Methyl{3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Ethyl {3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Prop-2-yn-1-yl {3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; Propyl {3-chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate; N-{3-Chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclopentanecarboxamide; N-{3-Chloro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}cyclohexanecarboxamide; (5S)-7-(5-Fluoropyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(5-Bromopyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Ethylpyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 4-{2-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide; N-Cyclopropyl-4-{2-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}benzamide; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(4-methoxyphenyl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-3-ylpyrimidin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 5-{2-[(5S)-2-(cis-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyrimidin-5-yl}-N,N-dimethylpyridine-2-carboxamide; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-(5-pyridin-4-ylpyrimidin-2-yl)-2,7-diazaspiro[4.5]decan-1-one; 4-{5-Chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-N-cyclopropylbenzamide; 5′-Chloro-N-ethyl-6′-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3,3′-bipyridine-6-carboxamide; 2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]isonicotinonitrile; Methyl{4-[(5S)-2-(cis-4-hydroxy-4-methylcyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3-methylphenyl}carbamate; Prop-2-yn-1-yl {6-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; (5)-7-(5-Fluoropyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5)-7-(5-Ethylpyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(Tetrahydro-2H-pyran-4-yl)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(4-Methoxypyrimidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2-Fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(1H-pyrazol-1-yl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(3-methyl-1H-pyrazol-1-yl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-{5-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-2-yl}-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-pyrimidin-2-yl-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[5-(2-oxopyridin-1(2H)-yl)pyrimidin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(2,5-Difluoropyridin-3-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3,5-Difluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Fluoro-4-(trifluoromethyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Bromo-2-chloropyridin-3-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Bromo-3-fluoropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Bromo-3-chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Bromo-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; Methyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate; Ethyl {6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate; Propyl {6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate; Prop-2-yn-1-yl {6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methylpyridin-3-yl}carbamate; Methyl{6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; Ethyl {6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; Propyl {6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; Prop-2-yn-1-yl {6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-methoxypyridin-3-yl}carbamate; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(cis-4-Hydroxycyclohexyl)-7-[3-methoxy-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Chloro-5-phenylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(4-methoxyphenyl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 4-{5-Chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}benzamide; (5S)-7-(5-Chloro-3,4′-bipyridin-6-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 5′-Chloro-6′-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-N,N-dimethyl-3,3′-bipyridine-6-carboxamide; 5′-Chloro-N,N-diethyl-6′-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-3,3′-bipyridine-6-carboxamide; 4-{5-Chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}-N,N-dimethylbenzamide; Methyl{5-chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Ethyl {5-chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Propyl {5-chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; Prop-2-yn-1-yl {5-chloro-6-[(5S)-2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]pyridin-3-yl}carbamate; (5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Chloro-3,3′-bipyridin-6-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; 6-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-2-methylnicotinonitrile; 2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-4,6-dimethylnicotinonitrile; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-[2-(trifluoromethyl)quinazolin-4-yl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-Cyclohexyl-7-[2-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Chloro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(3-Fluoro-4-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Fluoro-3-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-(5-Fluoro-6-methylpyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one; (5S)-2-(trans-4-Hydroxycyclohexyl)-7-(5-methylpyridin-2-yl)-2,7-diazaspiro[4.]decan-1-one; 2-[(5S)-2-(trans-4-Hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]-5-phenylnicotinonitrile; (5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one; (5S)-7-[3-Chloro-5-(2-oxo-1,3-oxazinan-3-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one; and (5S)-7-[3-Chloro-5-(2-oxopiperidin-1-yl)pyridin-2-yl]-2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one; or a pharmaceutically acceptable salt thereof.
 65. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 66. A method of modulating activity of 11βHSD1 or MR comprising contacting said 11βHSD1 or said MR with a compound of Formula I:

or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z; L is (CR¹²R¹³)_(q1), (CR¹²R¹³)_(q1)O(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)S(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), or (CR¹²R¹³)_(q1)CO(CR¹²R¹³)_(q2); Q is —(CR¹R²)_(m)-A; A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′; E is —(CR^(3a)R^(3b))_(n1)—, —(CR^(3a)R^(3b))_(n2)CO—, —(CR^(3a)R^(3b))_(n2)OCO—, —(CR^(3a)R^(3b))_(n2)SO—, —(CR^(3a)R^(3b))_(n2)SO₂—, —(CR^(3a)R^(3b))_(n2)NR^(3c)—, —(CR^(3a)R^(3b))_(n3)CONR^(3c)—, —(CR^(3a)R^(3b))_(n2)NR^(3c)CO—, or a group of formula:

D¹, D², D³ and D⁴ are each N or CR¹⁵; R¹ and R² are each, independently, H or C₁₋₈ alkyl; R^(3a) and R^(3b) are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(C′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R¹⁶; R^(3c) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or CO—(C₁₋₄ alkyl); R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(c′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R¹⁴; or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁶ and R⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁸ and R⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R¹⁰ and R¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁴ and R⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁶ and R⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁴ and R⁹ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁴ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁶ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁹ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; R¹² and R¹³ are each, independently, H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′)R^(d′); R¹⁴ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′)R^(d′); R¹⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″R) ^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), or S(O)₂NR^(c″)R^(d″); R¹⁶ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′R) ^(d′); W, W′ and W″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; X, X′ and X″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; Y, Y′ and Y″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; Z, Z′ and Z″ are each, independently, H, halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(d), NR^(e)S(O)₂R^(b), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d); wherein two —W—X—Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″; wherein two —W′—X′—Y′-Z′ attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″; wherein —W—X—Y-Z is other than H; wherein —W′—X′—Y′-Z′ is other than H; wherein —W″—X″—Y″-Z″ is other than H; R^(a), R^(a′) and R^(a″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(b), R^(b′) and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(c) and R^(d) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c) and R^(d) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c′) and R^(d′) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c′) and R^(d′) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c″) and R^(d″) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c″) and R^(d″) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(e) and R^(f) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(e) and R^(f) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; m is 0, 1, 2 or 3; n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; p is 0, 1 or 2; q1 is 0, 1 or 2; q2 is 0, 1 or 2; and r is 0, 1 or
 2. 67. The method of claim 66 wherein said modulating is inhibiting.
 68. A method of treating a disease in a patient, wherein said disease is associated with expression or activity of 11βHSD1 or MR, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

or pharmaceutically acceptable salt or prodrug thereof, wherein: Cy is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W—X—Y-Z; L is (CR¹²R¹³)_(q1), (CR¹²R¹³)_(q1)O(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)S(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), (CR¹²R¹³)_(q1)SO₂(CR¹²R¹³)_(q2), or (CR¹²R¹³)_(q1)CO(CR¹²R¹³)_(q2); Q is —(CR¹R²)_(m)-A; A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 —W′—X′—Y′-Z′; E is —(CR^(3a)R^(3b))_(n1)—, —(CR^(3a)R^(3b))_(n2)CO—, —(CR^(3a)R^(3b))_(n2)OCO—, —(CR^(3a)R^(3b))_(n2)SO—, —(CR^(3a)R^(3b))_(n2)SO₂—, —(CR^(3a)R^(3b))_(n2)NR^(3c)—, —(CR^(3a)R^(3b))_(n3)CONR^(3c)—, —(CR^(3a)R^(3b))_(n2)NR^(3c)CO—, or a group of formula:

D¹, D², D³ and D⁴ are each N or CR¹⁵; R¹ and R² are each, independently, H or C₁₋₈ alkyl; R^(3a) and R^(3b) are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(C′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R¹⁶; R^(3c) is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or CO—(C₁₋₄ alkyl); R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each, independently, H, OC(O)R^(a′), OC(O)OR^(b′), C(O)OR^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(a′), NR^(c′)C(O)OR^(b′), S(O)R^(a′), S(O)NR^(c′)R^(d′), S(O)₂R^(a′), S(O)₂NR^(c′)R^(d′), OR^(b′), SR^(b′), halo, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by R¹⁴; or R⁴ and R⁵ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁶ and R⁷ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁸ and R⁹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R¹⁰ and R¹¹ together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁴ and R⁶ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁶ and R⁸ together with the carbon atom to which they are attached form a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocycloalkyl group which is optionally substituted by R¹⁴; or R⁴ and R⁹ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁴ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁶ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; or R⁹ and R¹⁰ together form a C₁₋₃ alkylene bridge which is optionally substituted by R¹⁴; R¹² and R¹³ are each, independently, H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′)R^(d′); R¹⁴ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′)R^(d′); R¹⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″R) ^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), or S(O)₂NR^(c″)R^(d″); R¹⁶ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), or S(O)₂NR^(c′R) ^(d′); W, W′ and W″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; X, X′ and X″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, oxo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; Y, Y′ and Y″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, COO, CONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆ alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionally substituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; Z, Z′ and Z″ are each, independently, H, halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(d), NR^(e)S(O)₂R^(b), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d); wherein two —W—X—Y-Z attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″; wherein two —W′—X′—Y′-Z′ attached to the same atom optionally form a 3-20 membered cycloalkyl or heterocyloalkyl group, each optionally substituted by 1, 2 or 3 —W″—X″—Y″-Z″; wherein —W—X—Y-Z is other than H; wherein —W′—X′—Y′-Z′ is other than H; wherein —W″—X″—Y″-Z″ is other than H; R^(a), R^(a′) and R^(a″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; heterocycloalkyl, heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(b), R^(b′) and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R^(c) and R^(d) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c) and R^(d) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c′) and R^(d′) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c′) and R^(d′) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(c″) and R^(d″) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(c″) and R^(d″) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R^(e) and R^(f) are each, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with H, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R^(e) and R^(f) together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; m is 0, 1, 2 or 3; n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; p is 0, 1 or 2; q1 is 0, 1 or 2; q2 is 0, 1 or 2; and r is 0, 1 or
 2. 69. The method of claim 68 wherein said disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, depression, dementia, glaucoma, cardiovascular disorders, osteoporosis, inflammation, a cardiovascular, renal or inflammatory disease, heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome or general aldosterone-related target organ damage. 